Pyrazole, triazole and tetrazole orexin receptor antagonists

ABSTRACT

The present invention is directed to pyrazole, triazole and tetrazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the pyrazole, triazole, and tetrazole compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behavior (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to pyrazole, triazole, and tetrazolecompounds which are antagonists of orexin receptors. The presentinvention is also directed to uses of the pyrazole, triazole, andtetrazole compounds described herein in the potential treatment orprevention of neurological and psychiatric disorders and diseases inwhich orexin receptors are involved. The present invention is alsodirected to pharmaceutical compositions comprising these compounds. Thepresent invention is also directed to uses of these pharmaceuticalcompositions in the prevention or treatment of such diseases in whichorexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

In embodiment no. 1, the present invention provides compounds of theformula I:

wherein:

-   X is N or C(R⁷);-   Y is N or C(R⁶), wherein when Y is N then X is also N;-   A is selected from the group consisting of phenyl, naphthyl and    heteroaryl;-   R^(1a), R^(1b) and R^(1c) are independently selected from the group    consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents (e.g., 1-4 substituents) selected from R⁴,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents (e.g., 1-4        substituents) selected from R⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents (e.g., 1-4 substituents) selected from R⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        (e.g., 1-4 substituents) selected from R⁴,    -   (10) —(C═O)_(m)—NR¹⁰R^(1 1,) wherein R¹⁰ and R¹¹ are        independently selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R⁴,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R⁴,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R⁴,        -   (f) phenyl, which is unsubstituted or substituted with R⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R³ is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl, which is    unsubstituted or substituted with one or more substituents selected    from R⁴;-   R⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH₂,    -   (7) —NH—C₁₋₆alkyl,    -   (8) —NO_(2,)    -   (9) phenyl,    -   (10) heterocycle,    -   (11) —CO₂H, and    -   (12) —CN;-   R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, —O—C₁₋₆alkyl, —NH_(2,) —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (4) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH2, —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl —OH,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —(C═O)O—C₁₋₆alkyl,    -   (7) —CN,    -   (8) —(C═O)NH₂,    -   (9) —(C═O)NH—C₁₋₆alkyl, and    -   (10) —(C═O)NH—O—C₁₋₆alkyl;-   R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, —O—C₁₋₆alkyl, —NH_(2,) —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (4) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH_(2,)        —NH—C₁₋₆alkyl, —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl        is unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl —OH,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —(C═O)O—C₁₋₆alkyl,    -   (7) —CN,    -   (8) —(C═O)NH₂,    -   (9) —(C═O)NH—C₁₋₆alkyl, and    -   (10) —(C═O)NH—O—C₁₋₆alkyl;-   R⁷ is selected from the group consisting of:    -   (1) hydrogen and    -   (2) C₁₋₆alkyl, or        a pharmaceutically acceptable salt thereof.

In embodiment no. 2, the present invention provides a compound of theformula I or a pharmaceutically acceptable salt thereof, wherein A isselected from the group consisting of phenyl, pyridyl, thienyl,pyrazinyl, and pyrazolo[1,5-a]pyridinyl; and R^(1a), R^(1b), R^(1c), R³and R⁵ are as defined in embodiment no. 1.

In embodiment no. 3, the present invention provides a compound of theformula Ia

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are as defined in embodimentno. 1; or a pharmaceutically acceptable salt thereof.

In embodiment no. 4, the present invention provides a compound of theformula Ia′

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are as defined in embodimentno. 1; or a pharmaceutically acceptable salt thereof.

In embodiment no. 5, the present invention provides a compound of theformula Ia″

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are as defined in embodimentno. 1; or a pharmaceutically acceptable salt thereof.

In embodiment no. 6, the present invention provides a compound of theformula Ib

wherein R^(1a), R^(1b), R³ and R⁵ are as defined in embodiment no. 1; ora pharmaceutically acceptable salt thereof.

In embodiment no. 7, the present invention provides a compound of theformula Ib′

wherein R^(1a) R^(1b), R³ and R⁵ are as defined in embodiment no. 1; ora pharmaceutically acceptable salt thereof.

In embodiment no. 8, the present invention provides a compound of theformula Ib″

wherein R^(1a), R^(1b), R³ and R⁵ are as defined in embodiment no. 1; ora pharmaceutically acceptable salt thereof.

In embodiment no. 9, the present invention provides a compound of theformula I, Ia′, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein Y is C(R⁶), and R^(1a), R^(1b), R^(1c),R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 10, the present invention provides a compound of theformula I, Ia′, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein X is N and Y is C(R⁶), and R^(1a),R^(1b), R^(1c), R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 11, the present invention provides a compound of theformula I, Ia′, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein X is C(R⁷) and Y is C(R⁶), and R^(1a),R^(1b), R^(1c), R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 12, the present invention provides a compound of theformula I, Ia, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein X is N and Y is N, and R^(1a), R^(1b),R^(1c), R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 13, the present invention provides a compound as setforth in any one of embodiment nos. 9-11, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is hydrogen or methyl. In embodimentno. 14, R⁶ is hydrogen.

In embodiment no. 15, the present invention provides a compound as setforth in embodiment no. 9 or 11, or a pharmaceutically acceptable saltthereof, wherein R⁷ is hydrogen or methyl. In embodiment no. 16, R⁷ ishydrogen.

In embodiment no. 17, the present invention provides a compound of theformula I, Ia, Ia′, or Ia″, wherein R^(1a), R^(1b) and R^(1c) areindependently selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —CN, and    -   (7) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂;        and R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 18, the present invention provides a compound of theformula I, Ia, Ia′, or Ia″, wherein R^(1a), R^(1b) and R^(1c) areindependently selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen or methoxy,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (5) —C₃₋₆cycloalkyl, wherein said —C₃₋₆cycloalkyl is selected        from the group consisting of cyclopropyl and cyclobutyl, which        is unsubstituted or substituted with halogen or CN;    -   (6) heterocyclyl, wherein heterocyclyl is selected from the        group consisting of pyrazolyl, triazolyl, tetrazolyl,        oxadiazolyl, pyridyl, and pyrrolidinyl, which is unsubstituted        or substituted with C₁₋₆alkyl,    -   (7) phenyl; and    -   (8) —S—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen;        and R³ and R⁵ are as defined in embodiment no. 1.

In embodiment no. 19, the present invention provides a compound of theformula I, Ia, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein R³ is methyl or ethyl, and R^(1a),R^(1b), R^(1c), and R⁵ are as defined in embodiment no. 1.

In embodiment no. 20, the present invention provides a compound of theformula I, Ia, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein R³ is methyl, and R^(1a), R^(1b),R^(1c), and R⁵ are as defined in embodiment no. 1.

In embodiment no. 21, the present invention provides a compound of theformula I, Ia, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from the groupconsisting of:

-   -   (1) —C(CH₃)₂OH,    -   (2) —CH(OH)CF₃,    -   (2) —CH(OH)CH₃,    -   (2) —C(OH)(CF₃)CH₃,    -   (3) —C(═O)OCH₃,    -   (4) bromo, and    -   (5) phenyl;        and R^(1a), R^(1b), R^(1c), and R³ are as defined in embodiment        no. 1.

In embodiment no. 22, the present invention provides a compound of theformula I, Ia, Ia′, Ia″, Ib, Ib′, or Ib″ or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is —C(CH₃)₂OH, and R^(1a), R^(1b),R^(1c), and R³ are as defined in embodiment no. 1.

In embodiment no. 23, the present invention provides compound of theformula I, Ia, Ia′, or Ia″, or a pharmaceutically acceptable saltthereof, wherein:

-   -   R^(1a), R^(1b), and R^(1c) are as defined in embodiment no. 18;    -   R³ is as defined in embodiment no. 19; and    -   R⁵ is as defined in embodiment no. 21.

In embodiment no. 24, the present invention provides compound of theformula I, Ia, Ia′, or Ia″, or a pharmaceutically acceptable saltthereof, wherein:

-   -   R^(1a), R^(1b), and R^(1c) are as defined in embodiment no. 18;    -   R³ is methyl; and    -   R⁵ is —C(CH₃)₂OH.

In embodiment no. 25, the present invention provides a compound as setforth in any one of embodiment nos. 17-24 or a pharmaceuticallyacceptable salt thereof, wherein X is N and Y is C(R⁶) and R⁶ ishydrogen or methyl.

In embodiment no. 26, the present invention provides a compound as setforth in any one of embodiment nos. 17-24 or a pharmaceuticallyacceptable salt thereof, wherein X is C(H) and Y is C(R⁶), and R⁶ ishydrogen or methyl.

In embodiment no. 25, the present invention provides a compound as setforth in any one of embodiment nos. 17-24 or a pharmaceuticallyacceptable salt thereof, wherein X is N and Y is N.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present invention include a compound which isselected from the group consisting of:

1-(2-((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile;

[1,1′-biphenyl]-2-yl((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-propylpyridin-3-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-propylphenyl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopropylphenyl)methanone;

(2-cyclopropylphenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

(2-(difluoromethoxy)pyridin-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

methyl3-((2R,5R)-5-(4-(2-hy-droxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)picolinate;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethyl)phenyl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanone;

2-{2-[(3R,6R)-6-methyl-1-({2-[(trifluoromethyl)sulfanyl]phenyl}carbonyl)piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

(2-ethoxyphenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperi-din-1-yl)methanone;

(2-(2,2-difluoroethoxy)pyridin-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopro-poxypyridin-3-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)phenyl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopropoxyphenyl)methanone;

(2-(2,2-difluoroethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone;

methyl2-((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)benzoate;

(2-(difluoromethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

2-{2-[(3R,6R)-1-({2-[(1S)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-({2-[(1R)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

methyl2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate;

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-phenyl-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-bromo-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

(5-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;

2-{2-[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[5-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[4-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[4-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazo}-4-yl}propan-2-ol;

2-(2-{(3R,6R)-6-methyl-1-[(3-pyridin-2-ylpyrazin-2-yl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[3-(1H-pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[2-(2-methoxyethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[6-methoxy-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-(2-{(3R,6R)-6-methyl-1-[(2-pyrrolidin-1-ylphenyl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-(2-{(3R,6R)-6-methyl-1-[(3-phenoxyphenyl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-{2-[(3R,6R)-1-{[2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[2-(methoxymethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-Methyl-1-(pyrazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-Methyl-1-{[3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-(2-{(3R,6R)-1-[(2-cyclopropylpyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;

1-{2-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}ethanol;

2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-(2-{(3R,6R)-1-[(2-ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-{2-[(3R,6R)-1-{[2-(difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol

2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-(2-{(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-(2-{(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-{2-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol;

2-(5-methyl-2-{(3R,6R)-6-methyl-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;

2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-tetrazol-5-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-6-methyl-1-[(2-propylphenyl)carbonyl]piperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-(1-{(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-(1-{(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethyl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-{[2-(difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-({2-[(1S)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-({2-[(1R)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-1-[(2-cyclobutylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-({2-[(trifluoromethyl)sulfanyl]phenyl}carbonyl)piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-1-[(2-ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-6-methyl-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[3-(1H-pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-1-[(2-cyclopropyl-6-methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-(1-{(3R,6R)-1-[(2-cyclobutyl-6-methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;

2-{1-[(3R,6R)-6-methyl-1-{[3-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

(1R)-2,2,2-trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol;

(1S)-2,2,2-trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol;

1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

(2R)-1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

(2S)-1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

2-{3-methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;and

2-{5-methyl-1-[(3R,6R)-6-methyl-1-}[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as 36Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals may betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof that could be useful inmedicine. The present invention may further be directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for antagonizing orexinreceptor activity or treating the disorders and diseases noted herein inhumans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μlassay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 μl assay buffer. 30 μl of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 μl,incubated for 5 min and finally 25 μl of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425 -1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity in theFLIPR assay with an IC₅₀ of about 5 nM to 2000 nM against the orexin-2receptor. Additional data is provided in the following Examples. Such aresult is indicative of the intrinsic activity of the compounds in useas antagonists of orexin-1 receptor and/or the orexin-2 receptor. Ingeneral, one of ordinary skill in the art would appreciate that asubstance is considered to effectively antagonize the orexin receptor ifit has an IC₅₀ of less than about 50 μM, preferably less than about 1000nM.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention could therefore potentially have utility intreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension;

congestive heart failure; conditions of the genital/urinary system;disorders of sexual function and fertility; adequacy of renal function;responsivity to anesthetics; mood disorders, such as depression or moreparticularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder, mood disorders due to a general medical condition,and substance-induced mood disorders; affective neurosis; depressiveneurosis; anxiety neurosis; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; acute neurological and psychiatricdisorders such as cerebral deficits subsequent to cardiac bypass surgeryand grafting, stroke, ischemic stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage; Huntington's Chorea; Huntington's disease and Tourettesyndrome; Cushing's syndrome/disease; basophile adenoma; prolactinoma;hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases;inflammatory bowel disease; gastric diskinesia; gastric ulcers;Froehlich's syndrome; adrenohypophysis disease; hypophysis disease;adrenohypophysis hypofunction; adrenohypophysis hyperfunction;hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia);functional or psychogenic amenorrhea; hypopituitarism; hypothalamichypothyroidism; hypothalamic-adrenal dysfunction; idiopathichyperprolactinemia; hypothalamic disorders of growth hormone deficiency;idiopathic growth deficiency; dwarfism; gigantism; acromegaly;amyotrophic lateral sclerosis; multiple sclerosis; ocular damage;retinopathy; cognitive disorders; idiopathic and drug-inducedParkinson's disease; muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, seizuredisorders, absence seisures, complex partial and generalized seizures;Lennox-Gastaut syndrome; cognitive disorders including dementia(associated with Alzheimer's disease, ischemia, trauma, vascularproblems or stroke, HIV disease, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia,other general medical conditions or substance abuse); delirium, amnesticdisorders or age related cognitive decline; schizophrenia or psychosisincluding schizophrenia (paranoid, disorganized, catatonic orundifferentiated), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced psychotic disorder; dissociateive disorders includingmultiple personality syndromes and psychogenic amnesias;substance-related disorders, substance use, substance abuse, substanceseeking, substance reinstatement, all types of psychological andphysical addictions and addictive behaviors, reward-related behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,addictive feeding, addictive feeding behaviors, binge/purge feedingbehaviors, dependence, withdrawal or relapse from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics); appetite, taste, eating or drinking disorders; movementdisorders, including akinesias and akinetic-rigid syndromes (includingParkinson's disease, drug-induced parkinsonism, postencephaliticparkinsonism, progressive supranuclear palsy, multiple system atrophy,corticobasal degeneration, parkinsonism-ALS dementia complex and basalganglia calcification), chronic fatigue syndrome, fatigue, includingParkinson's fatigue, multiple sclerosis fatigue, fatigue caused by asleep disorder or a circadian rhythm disorder, medication-inducedparkinsonism (such as neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, and dyskinesias [including tremor (suchas rest tremor, essential tremor, postural tremor and intention tremor),chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), restless leg syndrome and dystonia (includinggeneralised dystonia such as iodiopathic dystonia, drug-induceddystonia, symptomatic dystonia and paroxymal dystonia, and focaldystonia such as blepharospasm, oromandibular dystonia, spasmodicdysphonia, spasmodic torticollis, axial dystonia, dystonic writer'scramp and hemiplegic dystonia); neurodegenerative disorders includingnosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to patients (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: insulin sensitizers including (i)PPAR_(γ) antagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor a agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fabric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine;(5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosediscribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25)β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,N1e14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed in Pept. Sci.2002 Aug; 8(8): 461-75); (33) CNTF (Ciliary neurotrophic factors), suchas GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo),butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives,such as axokine (Regeneron); (35) monoamine reuptake inhibitors, such assibutramine; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, suchas phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,a-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H₃ antagonists; AMPAagonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin ∪ receptor agonists, andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention may beeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518,WO2009/143033 and WO2010/048012) or as illustrated herein. The followingabbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl;Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; Boc: tert-butyloxycarbonyl; BSA: bovine serum albumin; CbzCl: benzylchloroformate; CDI:carbonyl diimidazole; DCM: dichloromethane; DCE: dichloroethane; DEAD:diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMF:N,N-dimethylformamide; DMSO: dimethylsulfoxide; CH₂Cl₂: dichloromethane;EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N:triethylamine; EtOAc: ethylacetate; EtOH: ethanol; HCl: hydrogenchloride; HATU: (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate); HOAt: 1-hydroxy-7-aza-benzotriazole; HOBT:hydroxybenzotriazole hydrate; HPLC: high performance liquidchromatography; Hunig's base: N,N-diisopropylethylamine; MeOH: methanol;MgSO₄: magnesium sulfate; MTBE: methyl tert-butyl ether; NaHCO₃: sodiumbicarbonate; NaOH: sodium hydroxide; NMM: N-methylmorpholine; PyClu:1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate;rt: room temperature; SOCl₂: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF:tetrahydrofuran; TFA: trifluoracetic acid. The compounds of the presentinvention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

INTERMEDIATES Intermediate A 2-(1-Cyanocyclopropyl) benzoic acid

Step 1: Methyl 2-(1-cyanocyclopropyl)benzoate (A1)

To a solution of NaH (1.1 g, 26.2 mmol) in DMSO (20 mL) was added methyl2-(cyanomethyl)benzoate (2 g, 11.4 mmol); after stirring at RT undernitrogen for 1 h, 1-bromo-2-chloroethane (1.8 g, 12.6 mmol) was addedand the mixture stirred at RT for 2 h. The mixture was quenched with icewater (10 mL) and extracted with EtOAc (10 mL×3). The organic layerswere combined, dried over Na₂SO₄ and concentrated in vacuo to give thecrude compound, which was purified by column chromatography on silicagel (petroleum ether/EtOAc 20:1) to give the title compound (2 g) as asolid. MS (ESI) m/e (M+H⁺) detected.

Step 2: 2-(1-Cyanocyclopropyl)benzoic acid (Intermediate A)

To a solution of the product from step 1 in THF/MeOH/H₂O (3:1:1, 16 mL)was added lithium hydroxide in water (3 mL) and the mixture stirredovernight at RT. The THF and MeOH were removed in vacuo and theresulting solution acidified to pH ˜1 with HCl (1 N) to give acrystalline precipitate. The solid was isolated by filtration, washedwith water and dried in vacuo to afford intermediate A as a solid. MS(ESI) m/e (M+H⁺): 187.9.

Intermediate B 4-(Pyrimidin-2-yl)thiophene-3-carboxylic acid

Step 1: 4-Pyrimidin-2-yl-thiophene-3-carboxylic acid ethyl ester (B1)

To a degassed solution of 4-bromothiophene-3-carboxylic acid ethyl ester(1 g, 4.3 mmol), 2-tributylstannanylpyrimidine (1.587g, 4.3mmol) and CsF(1.3 g, 8.6 mmol) in DMF (5 mL) was added Pd(PPh₃)₄(0.5 g, 0.43 mmol)and CuI (0.16 g, 0.86 mmol). The mixture was heated under microwaveconditions at 110° C. for 45 minutes, cooled and diluted with sat NH₄Clsolution and water. The mixture was extracted with EtOAc (20 mL×5) andthe combined organic layers dried over Na₂SO₄, filtered and the filtrateconcentrated in vacuo. The residue was purified by chromatography onsilica gel (petroleum ether: EtOAc=10:1) to provide the title compound(1.06 g) as an oil. LRMS m/z (M+H) 235.0 found, 235.0 required.

Step 2: 4-Pyrimidin-2-yl-thiophene-3-carboxylic acid (Intermediate B)

The title compound was prepared from the product of step 1 using theprocedure described for the synthesis of compound F2. LRMS m/z (M+H)207.0 found, 207.0 required.

Intermediate C 2-(2H-Tetrazol-2-yl)benzoic acid

To a 20 mL microwave tube was charged 2-iodobenzoic acid (1.85 g, 7.46mmol), cesium carbonate (4.06 g, 12.5 mmol), copper(I) iodide (0.128 g,0.671 mmol), and DMA (8.0 mL). N ,N′-Dimethylglycine (0.131 g, 1.27mmol) and tetrazole (1.29 g, 18.4 mmol) were added, and the solutionirradiated in a microwave reactor at 100° C. for 1 hour. The reactionmixture was diluted with water and 1 N aqueous sodium hydroxide andwashed with EtOAc. The aqueous fraction was acidified with conc. HCl andextracted 2× with EtOAc. The combined organic fractions were washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography [0-85% (1% acetic acidin EtOAc) in hexanes], to provide the title compound. ¹H NMR (400 MHz,CD₃OD): ä7.72-7.84 (m, 3 H), 8.07 (dd, J=7.6, 1.6 Hz, 1 H), 8.90 (s, 1H) ppm. LRMS m/z (M+H) 191.1 found, 191.2.

Intermediate D 2-(2H)-1,2,3-Triazol-2-yl)thiophene-3-carboxylic acid

A solution of 2-bromo-3-thiophene carboxylic acid (1.50 g, 7.24 mmol),1H-1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g,14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) wassparged with nitrogen and heated to 75° C. for 96 h. The cooled reactionmixture was diluted with water, washed with ether, and acidified withconc. HCl. The acidic aqueous solution was extracted 3× with EtOAc andthe combined organic fractions washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The crude material was purified bysilica gel chromatography [0-70% (1% acetic acid in EtOAc) in hexanes],to provide the title compound as a solid. LRMS m/z (M+H) 196.2 found,196.1 required.

Intermediate E Potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate

Step 1: Methyl 2-bromothiophene-3-carboxylate (E1)

A solution of 2-bromo-3-thiophene carboxylic acid (3.35 g, 16.2 mmol) inmethanol (50 mL) was cooled to 0° C. and saturated with gaseous HCl. Thesolution was heated to 60° C. overnight, cooled and then concentrated invacuo. The residue was redissolved in EtOAc, washed with saturatedaqueous sodium bicarbonate and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo, providing methyl 2-bromothiophene-3-carboxylateas an oil. LRMS m/z (M+H) 221.1 found, 221.0 required.

Step 2: Methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate (E2)

A solution of the product from step 1 (1.74 g, 7.87 mmol),2-(tributylstannyl) pyrimidine (4.36 g, 11.81 mmol), CsF (4.78 g, 31.5mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in apressure vessel was sparged with nitrogen and treated with Pd(PPh₃)₄(0.455 g, 0.394 mmol). The mixture was sealed and heated at 120° C.overnight. The cooled reaction mixture was partitioned between EtOAc andwater and filtered through celite. The organic layer was washed withsaturated aqueous sodium bicarbonate and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (0-30% EtOAc in hexanes), to provide the titlecompound as a solid. LRMS m/z (M+H) 221.2 found, 221.1 required.

Step 3: Potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate(Intermediate E)

A solution of the product from step 2 (0.695 g, 3.16 mmol) and potassiumtrimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred atRT overnight, then diluted with ether and filtered through a glass frit.The solids were washed with ether, and the filtrate was concentrated invacuo, to provide the title compound as a beige solid. LRMS m/z (M+H)207.3 found, 207.1 required.

Intermediate F 4-(2H-1,2,3-Triazol-2-yethiophene-3-carboxylic acid

Step 1: 4-Bromo-thiophene-3-carboxylic acid ethyl ester (F1)

To a solution of 3,4-dibromothiophene (30 g, 0.12 mol) in THF (200 mL)at 0° C. was added i-PrMgCl (2.0 M solution in THF, 77 mL, 0.15 mol),keeping the temperature below 5° C. The resulting mixture was stirred at0-5° C. for 5 h, ethyl chloroformate (14.4 mL, 0.15 mol) added dropwiseat <10° C. and the resulting mixture warmed to RT, stirred overnight andquenched with the sat aqueous NH₄Cl. Most of the THF was then removed invacuo, water added and the mixture extracted with EtOAc (80 mL×4). Thecombined organic layers were dried over Na₂SO₄, filtered, the filtrateconcentrated in vacuo and the crude product purified by chromatographyon silica gel (petroleum ether: EtOAc=300:1) to provide the titlecompound (21 g) as an oil.

Step 2: 4-Bromo-thiophene-3-carboxylic acid (F2)

To a solution of the product from step 1 (10 g, 43 mmol) in methanol (60mL) was added sodium hydroxide (3.4 g, 86 mmol) and water (1 mL) and themixture was stirred at RT overnight. The mixture was concentrated invacuo, the residue diluted with water (30 mL) and extracted with EtOAc(25 mL×4). The pH of aqueous layer was adjusted to ˜3 with 1M HCl andthe aqueous phase extracted with EtOAc (25 mL×4). The combined extractswere dried over Na₂SO₄, filtered and the filtrate concentrated in vacuoto provide the title compound (7.9 g) as a solid. LRMS m/z (M+H) 206.9,208.9 found, 206.9, 208.9 required.

Step 3: 4-(2H-1,2,3-Triazol-2-yl)thiophene-3-carboxylic acid(Intermediate F)

To a mixture of the product from step 2 (7.9 g, 38 mmol), cesiumcarbonate (24.8 g,76 mmol) and CuI (2.88 g, 7.6 mmol) in DMF (200 mL)were added 2H-[1,2,3]triazole (5.24 g,76 mmol) andN,N′-dimethyl-cyclohexane-1,2-diamine (0.9 g, 6.5 mmol) and the mixturewas heated to 110° C. overnight. The cooled reaction mixture wasadjusted to ˜pH12 with 1M sodium hydroxide and extracted with EtOAc (50mL×3). The aqueous layer was adjusted to ˜pH 4 with 1M HCl and extractedwith EtOAc (50 mL×4). The extracts was dried over Na₂SO₄, filtered, thefiltrate concentrated in vacuo and the residue purified bychromatography on silica (Petroleum ether: EtOAc=10:1) to provide thetitle compound (4.1 g). LRMS m/z (M+H) 196.0 found, 196.0 required.

Intermediate G 5-(2H-1,2,3-Triazol-2-yl)isothiazole-4-carboxylic acid

Step 1: 5-Bromo-isothiazole-4-carboxylic acid (G1)

To a solution of isothiazole-4-carboxylic acid (1.70 g, 12.98 mmol) inTHF (17 ml) was added t-BuLi (29.95 mL) at −78° C., and then a solutionof CBr₄ (8.62 g, 25.96 mmol) in THF (10 ml) was added dropwise. Themixture was stirred at −78° C. for 2 h, quenched with addition ofsaturated aqueous NH₄Cl and extracted with EtOAc (50 mL×3). The aqueouslayer was adjusted to pH ˜1.5 by addition of HCl, and then extractedwith EtOAc (50 mL×3). The combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo providing the title compound (1.50g), which was used without further purification.

Step 2: 5-[1,2,3]Triazol-2-yl-isothiazole-4-carboxylic acid(Intermediate G)

To a solution of the product from step 1 (1.50 g, 7.25 mmol) in DMF (15mL) were added potassium carbonate (2.00 g, 14.5 mmol), CuI (138 mg,0.725 mmol) and 2H-1, 2, 3-triazole (0.6 g, 8.70 mmol) and the mixtureheated at 110° C. for 16 h. The cooled reaction mixture was filtered andextracted with EtOAc (50 mL×3). The aqueous layer was adjusted to pH˜1.5 by addition of HCl, and then extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by Prep-HPLC, providingthe title compound as a solid (121 mg).

Intermediate H 4-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesiumcarbonate (89.26 g, 274 mmol) and CuI (5.27 g, 27.4 mmol) in DMF (200mL) were added N,N′-dimethylcyclohexane-1,2-diamine (3.7 mL,23.3 mmol)and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture wasstirred at 110° C. overnight, cooled, concentrated in vacuo and dilutedwith water (150 mL). The aqueous layer was extracted with EtOAc (300mL×3). The aqueous layer was acidified with 2N HCl and extracted withEtOAc (300 mL×4). The combined organic layers were washed with brine(150 mL×3), dried over Na₂SO₄, filtered and the filtrate concentrated invacuo. The residue was purified by chromatography on silica gel(petroleum ether: EtOAc=100: 1˜5: 1) to provide the title compound(18.13 g) as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.

Intermediate I 2-Propylnicotinic acid

Step 1: Methyl 2-allylnicotinate (I1)

To a solution of methyl 2-chloronicotinate (300 mg, 1.75 mmol) indioxane/H₂O (2 mL/1 mL) were added2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (354 mg, 2.11 mmol),K₂CO₃ (605 mg, 4.39 mmol) and Pd(PPh₃)₄ (203 mg, 0.175 mmol) and theresulting mixture heated at 100° C. for 3 hours. The cooled mixture wasdiluted with water (10 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo and the crude product purified byPrep-TLC (9% EtOAc in petroleum ether) to give the title compound (200mg) as an oil. LRMS m/z (M+H) 178.2 found, 178.1 required.

Step 2: Methyl 2-propylnicotinate (I2)

To a solution of the product from step 1 (4.8 g, 27.1 mmol) in EtOAc(200 mL) was added Pd/C (500 mg, 10 wt %). The resulting mixture wasstirred under H₂ at RT overnight. The mixture was filtered andconcentrated in vacuo to give the title compound (4.7 g) as an oil whichwas used directly without further purification. LRMS m/z (M+H) 180.2found, 180.1 required.

Step 3: 2-Propylnicotinic acid (Intermediate I)

To a solution of the product from step 3 (4.7 g, 26.3 mmol) in MeOH /H₂O(40 mL/40 mL) was added LiOH.H₂O (1.65 g, 39.4 mmol) and the resultingmixture stirred RT overnight. The mixture was diluted with water (50 mL)and extracted with EtOAc (70 mL×4). The aqueous layer was acidified with2 M HCl to pH˜2 and extracted with EtOAc (200 mL×7). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo and the crude product purified by chromatography on silica (50%EtOAc in petroleum ether) to provide the title compound (3.4 g) as asolid. LRMS m/z (M+H) 166.1 found, 166.1 required.

Intermediate J 5-Methyl-2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylicacid

Step 1: Ethyl 2-amino-5-methylthiophene-3-carboxylate (J1)

A mixture of ethyl 2-cyanoacetate (9.7 g, 90 mmol), TEA (5.15 g, 51mmol) and sublimed sulfur in DMF (30 mL) was stirred at 15° C. for 15mins. Propionaldehyde (5.0 g, 90 mmol) was added dropwise, the reactionmixture stirred for 3 hours, diluted with EtOAc (70 mL) and filtered.The filtrate was washed with water and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica (petroleum ether: EtOAc=10:1 to 1:1) to givethe title compound (7.4 g). LCMS m/z (M+H) 186.2 found, 186.1 required.

Step 2: Ethyl 2-bromo-5-methylthiophene-3-carboxylate (J2)

A mixture of tert-butyl nitrite (6.67 g, 64.8 mmol) and CuBr₂ inacetonitrile (80 mL) was stirred at 0° C. for 30 mins and a solution ofthe product from step 1 (6.0 g, 32.4 mmol) in acetonitrile (100 mL)added dropwise. The reaction mixture was stirred for 4 h diluted withEtOAc (70 mL), washed with water and brine, dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by chromatography onsilica (petroleum ether: EtOAc=100:0 to 90:10) to give the titlecompound (4.1 g) as an oil.

Step 3: 2-Bromo-5-methylthiophene-3-carboxylic acid (J3)

A solution of the product from step 2 (3.0 g, 12 mmol) and LiOH.hydrate(1.51 g, 36 mmol) in 15 mL of ethanol and 15 mL of water was stirred atRT overnight. The reaction mixture was adjusted to ˜pH 3 with 1N HCl andconcentrated in vacuo. The residue was extracted with EtOAc (30 mL×3),and the combined organic layers were dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuo to give the title compound as a solid(350 mg), which was used in the next step without further purification.

Step 4: 5-Methyl-2-(2H-1,2,3-triazol-2-ypthiophene-3-carboxylic acid(Intermediate J)

To a solution of the product from step 3 (1.4 g, 6.33 mmol), cesiumcarbonate (6.17 g, 19.0 mmol) and CuI (0.12 g, 0.633 mmol) in DMF (30mL) was added N,N′-dimethyl-cyclohexane-1,2-diamine (0.1 mL) and1H-1,2,3-triazole (873 mL, 12.66 mmol). The resulting mixture wasstirred at 110° C. overnight and the cooled mixture concentrated invacuo, diluted with water (50 mL) and extracted with EtOAc (30 mL×3).The aqueous layer was acidified with 2N HCl and extracted with EtOAc (30mL×4). The combined organic layers were washed with brine (50 mL×3),dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. Theresidue was purified by chromatography on silica gel (petroleum ether:EtOAc=1: 1) to give the title compound (700 mg) as an solid. LCMS m/z(M+H) 210.0 found, 210.0 required.

Intermediate K 2-(2,2-Difluoroethoxy)nicotinic acid

To a suspension of 2,2-difluoroethanol (492 mg, 6.0 mmol) in DMF (10 mL)at 0° C. was added NaH (180 mg, 4.5 mmol), and the mixture stirred at 0°C. for 0.5 h. A suspension of 2-fluoronicotinic acid (423 mg, 3.0 mmol)and NaH (180 mg, 4.5 mmol) in DMF (5mL) was added dropwise at 0° C. andthe resulting mixture stirred at RT overnight. The mixture was dilutedwith water, acidified to pH-3 with 1M HCl and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo to give the crude product 2(350 mg) which was used directly without any further purification. LRMSm/z (M+H) 204.1 found, 204.0 required.

Intermediate L 2-(2,2,2-Trifluoroethoxy)nicotinic acid

Step 1: tert-Butyl4-(4,6-dimethylpyrimidin-2-yl)-1,4-diazepane-1-carboxylate (IntermediateL)

To 2,2,2-trifluoroethanol (600 mg, 6.0 mmol) in DMF (10 mL) at 0° C.,was added NaH (180 mg, 4.5 mmol). The resulting mixture was stirred at0° C. for 0.5 h, and a suspension of 2-fluoronicotinic acid (423 mg, 3.0mmol) and NaH (180 mg, 4.5 mmol) in DMF (5 mL) added dropwise at 0° C.The resulting mixture was stirred at RT overnight, water added and themixture adjusted pH-3 with 1M HCl and extracted with EtOAc (30 mL×3).The organic layers were combined, washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to give the title compound (340 mg)used directly without further purification. LRMS m/z (M+H) 222.0 found,222.0 required.

Intermediate M 2-(2-Methoxyethyl)benzoic acid

Step 1: (E)-Methyl 2-(2-methoxyvinyl)benzoate (M1)

To a suspension of (methoxymethyl)triphenylphosphonium bromide (9.44 g,27.4 mmol) in THF (50 mL) was added NaH (1.46 g, 36.6 mmol) at 0° C.portion wise. The mixture was stirred at 0° C. for 0.5 h and then asolution of methyl 2-formylbenzoate (3.0 g, 18.3 mmol) in THF (15 mL)added dropwise and the reaction mixture stirred at RT for 12 h. Themixture was diluted with water, extracted with EtOAc (30 mL×2) and thecombined organic layers washed with brine, dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by chromatography onsilica (petroleum ether: EtOAc=10:1 to 3:1) to give the title compound(2.3 g) as an oil.

Step 2: Methyl 2-(2-methoxyethyl)benzoate (M2)

To a solution of the product from step 1 (2.3 g, 11.9 mmol) in EtOAc (30mL) was added Pd/C (200 mg) at RT and the mixture was stirred at RTovernight under a balloon of H₂. The mixture was filtered and thefiltrate concentrated in vacuo to give the title compound (2.2 g), whichwas used directly in the next step.

Step 3: 2-(2-Methoxyethyl)benzoic acid (Intermediate M)

A mixture of the product from step 2 (2.2 g, 11.3 mmol) and LiOH (1.43g, 33.9 mmol) in methanol (15 mL) and water (15 mL) was stirred at RTovernight. The mixture was adjusted to ˜pH 3 with 1N HCl andconcentrated in vacuo. The residue was extracted with EtOAc (30 mL×3),and the combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to give the title compound as a solid(1.5 g), which was used in the next step without further purification.

Intermediate N 2-(4-Cyanotetrahydro-2H-pyran-4-yl)benzoic acid

Step 1: Methyl 2-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate (N1)

To a suspension of NaH (27.4 g, 0.69 mol, 60%) in DMF was added dropwisea solution of methyl 2-(cyanomethyl)benzoate (50 g, 0.29 mol) in DMF at0° C. under N₂. The mixture was stirred for 30 mins at that temperatureand 18-crown-6 (7.6 g, 0.03 mol) was added. The mixture was stirred for30 mins at 0° C., NaI (42.9 g, 0.29 mol) was added, followed by dropwiseaddition of a solution of bis(2-bromoethyl)ether (79.6 g, 0.34 mol) at0° C. The reaction mixture was stirred for 1 h and poured into a largeamount of ice-water. The resulting mixture was filtered to give thetitle compound as a solid (42.7 g). MS (ESI) m/e (M+H⁺): 246.0

Step 2: 2-(4-Cyanotetrahydro-2H-pyran-4-yl)benzoic acid (Intermediate N)

To a solution of the compound from step 1 (40 g) in MeOH/THF (480 mL,5:1) was added NaOH (2M, 326 mL). The reaction was stirred at 60-65° C.for 3h, cooled to RT and concentrated in vacuo. Water (300 mL) was addedthe pH adjusted to ˜1 with HCl (2M). The mixture was filtered to giveintermediate M (34 g) as a solid. MS (ESI) m/e (M−H^(|)): 230.0

Intermediate O 2-(2,2-Difluorocyclopropyl)benzoic acid

Step 1: Methyl 2-vinylbenzoate (O1)

To a solution of methyl 2-bromobenzoate (1.2 g, 5.5 mmol) indioxane/water (15 mL/0.6 mL) were added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.7 g, 11.1 mmol),K₂CO₃ (1.53 g, 11.1 mmol) and Pd(dppf)Cl₂ (0.4 g) and the resultingmixture stirred at 100° C. overnight. The cooled mixture was dilutedwith water (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andthe filtrate concentrated in vacuo. The residue was purified bypreparative TLC (9.1% EtOAc in petroleum ether) to give the titlecompound (0.7 g) as an oil.

Step 2: Methyl 2-(2,2-difluorocyclopropyl)benzoate (O2)

A mixture of the product from step 1 (500 mg, 3.09 mmol) and KI (1.15 g,6.94 mmol) in DME (27.8 mg, 0.31 mmol) and dioxane (461.7 mg, 5.25 mmol)was stirred at 120° C. for 5 minutes. TMSCl (667 mg, 6.17 mmol) andmethyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.2 g, 6.17 mmol) wereadde and the resulting mixture stirred at 120° C. for 24 h. Water wasadded to the cooled mixture and the mixture extracted with EtOAc (10mL×3). The organic layers were combined, dried over Na₂SO₄, filtered andthe filtrate concentrated in vacuo. The residue was purified bypreparative HPLC to afford the title compound (200 mg) as a solid. LRMSm/z (M+H) 213.1 found, 213.2 required.

Step 3: 2-(2,2-Difluorocyclopropyl)benzoic acid (Intermediate O).

A solution of the product from step 2 (170 mg, 0.8 mmol) andLiOH^(·)H₂O(23 mg, 0.55 mmol) in THF: H₂O: MeOH (2:2:1) was stirred at0° C. overnight. The mixture was diluted wit water (6 mL), then adjustedto pH ˜2 with 1 M HCl and extracted with EtOAc (8 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and the filtrate concentrated in vacuo. The residue waspurified by preparative HPLC to give the title compound (80 mg) as asolid. LRMS m/z (M+H) 199.0 found, 199.2 required.

Intermediate P 2-Cyclobutyl-6-methoxynicotinic acid

Step 1: Methyl 2-chloro-6-methoxynicotinate (P1)

To a solution of 2-chloro-6-methoxynicotinic acid (5 g, 26.7 mmol) in amixture of DCM (50 mL) and MeOH (5 mL) at 0° C. was added(trimethylsilyl) diazomethane (16.0 mL, 32.0 mmol) dropwise. The mixturewas stirred at 0° C. for 10 min, quenched with acetic acid (4 mL), andextracted with DCM (50 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate concentrated in vacuo to give thetitle compound (5 g) as a solid used without further purification. LRMSm/z (M+H) 202.2, 204.2 found, 202.2, 204.2 required.

Step 2: Methyl 2-cyclobutyl-6-methoxynicotinate (P2)

To a solution of the product from step 1 (1.0 g, 4.96 mmol) in THF (10.0mL) at RT were added cyclobutylzinc (II) bromide (19.8 mL, 0.5M, 9.92mmol) and Pd(PPh₃)₄ (1.15 g, 0.99 mmol). The resulting mixture wasstirred at 80° C. under overnight, cooled to RT, poured into water (50mL) and extracted with EtOAc (50 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. Theresidue was purified by chromatography on silica (petroleum ether) togive the title compound (600 mg) as an oil. LRMS m/z (M+H) 222.2 found,222.2 required.

Step 3: 2-Cyclobutyl-6-methoxynicotinic acid (Intermediate P).

To a solution of the product from step 2 (600 mg, 2.71 mmol) in MeOH (10mL) and water (4 mL) at RT was added sodium hydroxide (542 mg, 13.6mmol). The resulting mixture was stirred at RT overnight, diluted withwater, acidified with 1N HCl and extracted with EtOAc (50 mL×2). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuo. The residue was purified by preparativeTLC (50% EtOAc in petroleum ether) to give the title compound (500 mg)as a solid. LRMS m/z (M+H) 208.2 found, 208.2 required.

Intermediate Q 3-(2H-1,2,3-Triazol-2-yepyrazine-2-carboxylic acid

Step 1: 3-(2H-1,2,3-Triazol-2-yl)pyrazine-2-carboxylic acid(Intermediate Q)

To a solution of 3-chloropyrazine-2-carboxylic acid (5.0 g, 31.5 mmol)in DMF (100 mL) were added K₂CO₃ (10.9 g, 79 mmol), CuI (1.2 g, 6.31mmol) and 2H-1,2,3-triazole (4.36 g, 63.1 mmol). The resulting mixturewas stirred at 120° C. overnight, cooled to RT and acidified with HCl(2M) to pH˜3. After filtration, the filtrate was concentrated in vacuo.The residue was purified by chromatography on silica (EtOAc) to givecrude product (1.5 g) as a solid, which was further purified bypreparative HPLC to afford the title compound (850 mg) as a solid. LRMSm/z (M+H) 192.2 found, 192.0 required.

EXAMPLE 1

1-(2-((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile Step 1: Methyl2H-1,2,3-triazole-4-carboxylate (1)

A mixture of 2H-1,2,3-triazole-4-carboxylic acid (6.0 g, 53 mmol) inSOCl₂ (50 mL) was stirred at 70° C. for 40 minutes . The cooled mixturewas concentrated in vacuo to give crude 2H-1,2,3-triazole-4-carbonylchloride which was added to MeOH (50 mL) dropwise and the mixture wasstirred for 2 minutes. The mixture was concentrated in vacuo andrecrystallized from MeOH to give the title compound (6.5 g) as a solid.LRMS m/z (M+H) 128.2 found, 128.1 required.

Step 2: (2R,5R)-Benzyl5-(4-(methoxycarbonyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carboxylate(2)

To a solution of the product from step 1 (6.5 g, 50.8 mmol),(2R,5S)-benzyl 5-hydroxy-2-methylpiperidine-1-carboxylate(WO2013/059222) (12.6 g, 50.8 mmol) and Ph₃P (26.6 g, 101.6 mmol) in THF(300 mL) at 0° C. was added DIAD (20.5 g, 101.6 mmol). The mixture wasstirred at RT for 16 h, concentrated in vacuo and the residue purifiedby Prep-HPLC to give the title compound (7.0 g) as an oil. LRMS m/z(M+H) 359.1 found, 359.2 required.

Step 3: (2R,5R)-Benzyl5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carboxylate(3)

To a solution of the product from step 2 (7.0 g, 20 mmol) in THF at 0°C., (150 mL) was added methylmagnesium bromide (20.0 mL, 60 mmol, 3M inether) and the resulting mixture stirred at 0° C. for 2 h. Saturatedaqueous NH₄Cl was added and the mixture extracted with EtOAc (200 mL×3).The organic layers were combined, dried over MgSO₄, filtered andconcentrated in vacuo to give the title compound (6.0 g) as an oil. LRMSm/z (M−OH) 341.3 (M−OH) found, 341.2 required.

Step 4:2-(2-((3R,6R)-6-Methylpiperidin-3-yl)-2H-1,2,3-triazol-4-yl)propan-2-ol(4)

To a solution of the product from step 3 (6.0 g, 16.7 mmol) in EtOH (150mL) was added Pd/C (600 mg, 10 wt %) at RT. The resulting mixture wasstirred under a balloon of H₂ for 2 h. The mixture was filtered andconcentrated in vacuo to give the title compound (4.0 g) as an oil,which was used directly without further purification. LRMS m/z (M+H)225.3 found, 225.2 required.

Step 5: 1-(242R ,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile(Example 1)

A mixture of HATU (122 mg, 0.320 mmol), 2-(1-cyanocyclopropyl) benzoicacid (Intermediate A) (30 mg, 0.16 mmol), DIEA (62 mg, 0.48 mmol) in DCM(3 mL) was stirred at 0° C. for 10 minutes. The product from step 4(36.2 mg, 0.160 mmol) was then added and the resulting mixture stirredat RT for 16 h. The mixture was concentrated in vacuo and the residuewas purified by Prep-HPLC to give the title compound (9.4 mg) as an oil.LRMS m/z (M+Na) 416.1 found, 416.2 required.

The following compounds were prepared according to the methodologyherein and the general procedure of step 5 provided in Example 1. Thestarting materials are either commercially available or may be preparedas described in the synthesis of intermediates, or may be prepared fromcommercially available reagents using conventional reactions well knownin the art.

Ex. Structure Name Mass [M + H]+ 2

[1,1′-Biphenyl]-2-yl((2R,5R)-5-(4- (2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1- yl)methanone Calc′d 405.2, found387.2 (M − OH), 427.2 (M + Na) 3

((2R,5R)-5-(4-(2-Hydroxypropan-2- yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2- propylpyridin-3-yl)methanone Calc′d 372.2,found 372.2 4

((2R,5R)-5-(4-(2-Hydroxypropan-2- yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2- propylphenyl)methanone Calc′d 371.2, found353.2 (M − OH), 393.2 (M + Na) 5

((2R,5R)-5-(4-(2-Hydroxypropan-2- yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2- isopropylphenyl)methanone Calc′d 371.2, found353.2 (M − OH), 393.2 (M + Na) 6

(2-Cyclopropylphenyl)((2R,5R)-5- (4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2- methylpiperidin-1-yl)methanone Calc′d 369.2,found 351.2 (M − OH), 393.1 (M + Na) 7

(2-(Difluoromethoxy)pyridin-3- yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3- triazol-2-yl)-2-methylpiperidin-1-yl)methanone Calc′d 396.2, found 378.1 (M − OH), 418.1 (M + Na) 8

Methyl 3-((2R,5R)-5-(4-(2-hy- droxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1- carbonyl)picolinate Calc′d 388.2, found370.1 (M − OH), 410.1 (M + Na) 9

((2R,5R)-5-(4-(2-Hydroxypropan-2- yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2- trifluoroethyl)phenyl)methanone Calc′d411.2, found 393.1 (M − OH), 433.1 (M + Na) 10

((2R,5R)-5-(4-(2-Hydroxypropan-2- yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(4-methyl- 1H-pyrazol-1-yl)pyridin-3-yl)methanone Calc′d 410.2, found 410.2 11

2-{2-[(3R,6R)-6-Methyl-1-({2- [(trifluoromethyl)sulfanyl]pheny}carbonyl)piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d429.1, found 411.1 (M − OH),

EXAMPLE 12

(2-Ethoxyphenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperi-din-1-yl)methanone(Example 12)

A mixture of HATU (251 mg, 0.66 mmol), 2-ethoxybenzoic acid (37.0 mg,0.22 mmol), DIEA (85.2 mg, 0.66 mmol) in DCM (3 mL) at 0° C. was stirredfor 10 min and piperidine intermediate 4 (Example 1 step 4) (50 mg, 0.22mmol) was added and the resulting mixture stirred at RT for 16 h. Themixture was concentrated in vacuo and the residue purified by Prep-HPLCto give the title compound (8.3 mg) as an oil. LRMS m/z (M+Na) 395.2found, 395.2 required.

EXAMPLE 13

(2-(2,2-Difluoroethoxy)pyridin-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone (Example 13)

A mixture of HATU (152 mg, 0.4 mmol), 2-(2,2-difluoroethoxy)nicotinicacid (40 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C.was stirred for 10 min, then piperidine intermediate 4 (Example 1 step4) (50 mg, 0.22 mmol) added and the resulting mixture stirred at RT for3 h. The mixture was concentrated in vacuo and the residue was purifiedby Prep-HPLC to give the title compound (47 mg) as an oil. LRMS m/z(M+Na) 432.1 found, 432.2 required.

EXAMPLE 14

((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone(Example 14)

A mixture of HATU (152 mg, 0.4 mmol), 2-(2,2,2-trifluoroethoxy)nicotinicacid (41 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C.was stirred for 10 min and piperidine intermediate 4 (Example 1 step 4)(50 mg, 0.22 mmol) added and the mixture stirred at RT for 3 h. Themixture was concentrated in vacuo and the residue purified by Prep-HPLCto give the title compound (38 mg) as an oil. LRMS m/z (M+Na) 450.1(M+Na) found, 450.2 required.

EXAMPLE 15

((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopro-poxypyridin-3-yl)methanone(Example 15)

A mixture of HATU (152 mg, 0.4 mmol), 2-isopropoxynicotinic acid (36 mg,0.2 mmol) and DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C. was stirredfor 10 min and piperidine intermediate 4 (Example 1 step 4) (50 mg, 0.22mmol) added and the resulting mixture stirred at RT for 3 h. The mixturewas concentrated in vacuo and the residue purified by Prep-HPLC to givethe title compound (46 mg) as an oil. LRMS m/z (M+Na) 410.2 found, 410.2required.

EXAMPLE 16

((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)phenyl)methanone(Example 16)

A mixture of HATU (152 mg, 0.4 mmol), 2-(2,2,2-trifluoroethoxy)benzoicacid (50 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C.was stirred for 10 min and piperidine intermediate 4 (Example 1 step 4)(50 mg, 0.22 mmol) was added and the resulting mixture stirred at RT for3 h. The mixture was concentrated in vacuo and the residue purified byPrep-HPLC to give the title compound (43 mg) as an oil. LRMS m/z (M+Na)449.1 found, 449.2 required.

EXAMPLE 17

((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopropoxyphenyl)methanone(Example 17)

A mixture of HATU (152 mg, 0.4 mmol), 2-isopropoxybenzoic acid (50 mg,0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C. was stirred for10 min and piperidine intermediate 4 (Example 1 step 4) (50 mg, 0.22mmol) added and the resulting mixture stirred at RT for 3 h. The mixturewas concentrated in vacuo and the residue purified by Prep-HPLC to givethe title compound (28 mg) as an oil. LRMS m/z (M+Na) 409.2 found, 409.2required.

EXAMPLE 18

(2-(2,2-Difluoroethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone(Example 18)

A mixture of HATU (152 mg, 0.4 mmol), 2-(2,2-difluoroethoxy)benzoic acid(40 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C. wasstirred for 10 min and piperidine intermediate 4 (Example 1 step 4) (50mg, 0.22 mmol) added and the mixture stirred at RT for 3 h. The mixturewas concentrated in vacuo and the residue purified by Prep-HPLC to givethe title compound (30 mg) as an oil. LRMS m/z (M+Na) 431.1 found, 431.2required.

EXAMPLE 19

((2R,5R)-5-(4-(2-Hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone(Example 19)

A mixture of HATU (152 mg, 0.4 mmol), 2-(trifluoromethoxy)benzoic acid(41 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DMF (3 mL) at 0° C. wasstirred for 10 min and piperidine intermediate 4 (Example 1 step 4) (50mg, 0.22 mmol) added and the mixture stirred at RT for 3 h. Then themixture was concentrated in vacuo and the residue purified by Prep-HPLCto give the title compound (35 mg) as an oil. LRMS m/z (M+Na) 435.1found, 435.2 required.

EXAMPLE 20

Methyl2-((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)benzoate(Example 20)

A mixture of HATU (152 mg, 0.4 mmol), 2-(methoxycarbonyl)benzoic acid(36 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DCM (3 mL) was stirred at0° C. for 10 minutes. Then piperidine intermediate 4 (50 mg, 0.22 mmol)was added and the mixture was stirred at room temperature for 3 hours.Then the mixture was concentrated in vacuo and the residue was purifiedby Prep-HPLC to give the title compound (61.3 mg) as an oil. LRMS m/z(M+Na) 409.1 found, 409.2 required.

EXAMPLE 21

(2-(Difluoromethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone (Example 21)

A mixture of HATU (152 mg, 0.4 mmol), 2-(difluoromethoxy)benzoic acid(38 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) in DCM (3 mL) was stirred at0° C. for 10 minutes. Then piperidine intermediate 4 (50 mg, 0.22 mmol)was added and the mixture was stirred at room temperature for 3 hours.Then the mixture was concentrated in vacuo and the residue was purifiedby Prep-HPLC to give the title compound (59.3 mg) as an oil. LRMS m/z(M+Na) 417.1 found, 417.2 required.

EXAMPLES 22 AND 23

2-{2-[(3R,6R)-1-({2-[(1S)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol(Example 22) and2-{2-[(3R,6R)-1-({2-[(1R)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol(Example 23)

To a solution of piperidine intermediate 4 (62.7 mg, 0.28 mmol) in DMF(3 mL) was added HATU (190 mg, 0.5 mmol),2-(2,2-difluorocyclopropyl)benzoic acid (50 mg, 0.25 mmol) and DIPEA(81.3 mg, 0.63 mmol). The resulting mixture was stirred at RT overnight,concentrated in vacuo and the residue purified by preparative HPLC andthen chiral HPLC SFC (OD 250×30mm I.D.,5 um, CO₂/EtOH (0.1%)NH₃.H₂O=85/15 at 50 mL/min) to give Example 22 (22 mg, faster elutingisomer in SFC) as a solid and Example 23 (20 mg, slower eluting isomerin SFC) as a solid. Example 22: LRMS m/z (M−OH) 387.2 found, 405.2 (M+H)required. Example 23: LRMS m/z (M−OH) 387.1 found, 405.2 (M+H) required.

EXAMPLE 24

Methyl 2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate Step 1: (3S,6R)-6-Methylpiperidin-3-ol (5)

To a solution of(2R,5S)-benzyl-5-hydroxy-2-methylpiperidine-l-carboxylate (5 g, 20.1mmol) in MeOH at RT was added Pd/C (1.0 g, 10 wt %). The mixture wasstirred for 3 hours under an atmosphere of hydrogen gas, filtered andthe filtrate concentrated in vacuo to give the title compound (2.20 g)as an oil, used directly without purification. LRMS m/z 116.1 (M+H)found, 116.1 required.

Step 2: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R, 5 S)-5-hydroxy-2-methylpiperidin-1-yl)methanone (6)

To a solution of the product from step 1 (2.20 g, 19.1 mmol) and Et₃N(3.86 g, 38.2 mmol) in DCM (100 mL) at 0° C. was added2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (4.60 g, 22.2 mmol) dropwise.The mixture was stirred at 0° C. for 1 h, diluted with water (200 mL)and extracted with DCM (100 mL×3). The organic layers were combined,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by chromatography on silica (50% EtOAc in petroleum ether) togive the title compound (4.90 g) as a solid. LRMS m/z (M+H) 287.1 found,287.1 required.

Step 3: Methyl2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate(Example 24)

To a solution of methyl 2H-1,2,3-triazole-4-carboxylate (Example 1,step 1) (200 mg ,1.57 mmol), the product from step 2 (449 mg,1.57 mmol),and Ph₃P (812mg, 3.1 mmol) in THF at 0° C. was added DIAD (632mg, 3.1mmol). The resulting mixture was stirred at 25° C. for 4 h, concentratedin vacuo and the residue purified by preparative HPLC to give the titlecompound (60 mg) as an oil. LRMS m/z (M+H) 396.2 found, 396.2 required.

EXAMPLE 25

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone(Example 25)

To a solution of2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate(Example 24) (200 mg, 0.5 mmol) in THF (3 mL) was added methylmagnesiumbromide (0.5 mL, 1.5 mmol, 3M in ether) at 0° C. dropwise under nitrogenatmosphere . The resulting mixture was stirred at 0° C. for 2 hours.Then the mixture was quenched with saturated NH₄Cl aqueous solution,extracted with EtOAc (20 mL×3). The organic layers were combined, driedover MgSO₄, filtered and concentrated in vacuo to give the titlecompound (150 mg) as an oil. LRMS m/z (M+Na) 418.1 found, 418.2required.

EXAMPLES 26 AND 27

-   Scheme for the preparation of Example 26 and Example 27:

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone(Example 26)(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-l-yl)methanone(Example 27) Step 1:(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone(7)

To a solution of2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate(Example 24) (300 mg, 0.76 mmol) in DCM (5 mL) was added LiBH₄ (330 mg,0.160 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirredat 25° C. for 2 hours. The mixture was filtered and the filtrated waspurified by Prep-TLC (EtOAc) to give the title compound (250 mg) as asolid. LRMS m/z (M+H) 368.2 found, 368.2 required.

Step 2:2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carbaldehyde(8)

To a solution of the product from step 1 (100 mg, 0.3 mmol) in DCM (5mL)was added Dess-Martin reagent (254 mg, 0.6 mmol) at 0° C. under nitrogenatmosphere. The mixture was stirred at 25° C. for 2 hours. The mixturewas filtered and the filtrate was purified by Prep-TLC (EtOAc) to givethe title compound (70 mg) as a solid. LRMS m/z (M+H) 366.1 found, 366.2required.

Step 3: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone(Example 26) and(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-l-yl)methanone (Example 27)

To a solution of the product from step 2 (70 mg, 0.212 mmol) and CsF(36.5 mg, 0.240 mmol) in THF (4 mL) was added TMSCF₃ (43.0 mg, 0.300mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at 25°C. for 3 hours. Then the mixture was diluted with water (20 mL) andextracted with EtOAc (20 mL×3). The organic layers were combined, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by Prep-TLC (EtOAc) and then chiral SFC (Chiralpak AD-3 150×4.6mm I.D., 3 um, iso-propanol (0.05% DEA) in CO2 from 5% to 40% at2.5mL/min) to give Example 26 (16.3 mg, faster eluting isomer) andExample 27 (14.2 mg, slower eluting isomer) respectively as an oil.Example 26: LRMS m/z (M+H) 436.1 found, 436.2 required. Example 27: LRMSm/z (M+H) 436.1 found, 436.2 required.

EXAMPLE 28

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-phenyl-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone(Example 28)

To a solution of(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5S)-5-hydroxy-2-methylpiperidin-1-yl)methanone(Example 22, step 2) (80 mg, 0.28 mmol), Ph₃P (147 mg, 0.56 mmol) and4-phenyl-2H-1,2,3-triazole (81 mg, 0.56 mmol) in dry THF (1 mL) wasadded DEAD (96 mg, 0.56 mmol) at room temperature under nitrogenatmosphere. The mixture was stirred at ambient temperature overnight.The mixture was concentrated in vacuo, and the residue was purified byPrep-HPLC to give the title compound (77 mg) as an oil. LRMS m/z (M+H)414.2 found, 414.2 required.

The following compound was prepared according to the general procedureof step 1 provided in Example 28, substituting the appropriate triazolewith 4-bromo-2H-1,2,3-triazole. The starting materials are commerciallyavailable.

Ex. Structure Name Mass [M + H]+ 29

(2-(2H-1,2,3-triazol-2- yl)phenyl)((2R,5R)-5- (4-bromo-2H-1,2,3-triazol-2-yl)-2- methylpiperidin-1- yl)methanone Calc′d 416.1, 418.1found 416.1, 418.1

EXAMPLE 30

(5-Fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone(Example 30)

To a solution of2-(2-((3R,6R)-6-methylpiperidin-3-yl)-2H-1,2,3-triazol-4-yl) propan-2-ol(25 mg, 0.111 mmol) in DMF (0.5 mL) was added5-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (27.3 mg, 0.134mmol), EDC (42.7 mg, 0.223 mmol), Hunig's base (39 μL, 0.223 mmol), andHOAT (15 mg, 0.111 mmol). The resulting mixture was stirred overnight atRT. The mixture was diluted with water and EtOAc, extracted with EtOAc(1 mL×3). The organic layers were combined, dried over sodium sulfate,filtered and concentrated in vacuo. The crude mixture was purified bycolumn chromatography on silica gel (hexanes/EtOAc 1:2) to give thetitle compound (26 mg) as an oil. LRMS m/z (M+) 429.2 found, 429.2required.

The following compounds were prepared according to the methodologyherein or the general procedure of Example 30. The starting materialsare either commercially available or may be prepared as described in thesynthesis of intermediates, or may be prepared from commerciallyavailable reagents using conventional reactions well known in the art.

Mass Ex. Structure Name [M + H]+ 31

2-{2-[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 414.0,found 414.2 32

2-{2-[(3R,6R)-6-methyl-1-{[3-(2H-1,2,3- triazol-2-yl)thiophen-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d402.0, found 402.2 33

2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3- triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d402.0, found 402.2 34

2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 397.0, found 397.2 35

2-{2-[(3R,6R)-1-{[5-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 429.0,found 429.2 36

2-{2-[(3R,6R)-6-methyl-1-{[2-(3-methyl- 1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-olCalc′d 411.0, found 411.2 37

2-{2-[(3R,6R)-1-{[3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 429.0,found 429.2 38

2-{2-[(3R,6R)-1-{[5-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 414.0,found 414.2 39

2-{2-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 414.0,found 414.2 40

2-{2-[(3R,6R)-1-{[4-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 429.0,found 429.2 41

2-{2-[(3R,6R)-1-{[4-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 429.0,found 429.2 42

2-(2-{(3R,6R)-6-methyl-1-[(3-pyridin-2-ylpyrazin-2-yl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol Calc′d 408.0, found 408.2 43

2-{2-[(3R,6R)-6-methyl-1-{[3-(1H- pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d397.0, found 397.2 44

2-{2-[(3R,6R)-1-{[2-(2- methoxyethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 387.0,found 387.2 45

2-{2-[(3R,6R)-1-{[6-methoxy-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 427.0,found 427.2 46

2-{2-[(3R,6R)-6-methy]-1-{[3-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-olCalc′d 410.0, found 410.2 47

2-{2-[(3R,6R)-6-methyl-1-{[2-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-olCalc′d 411.0, found 411.2 48

2-{2-[(3R,6R)-1-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 429.0,found 429.2 49

2-(2-{(3R,6R)-6-methyl-1-[(2-pyrrolidin-1-ylphenyl)carbonyl]piperidin-3-yl}-2H- 1,2,3-triazol-4-yl)propan-2-olCalc′d 398.0, found 398.2 50

2-(2-{(3R,6R)-6-methyl-1-[(3- phenoxyphenyl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol Calc′d 421.0, found 421.2 51

2-{2-[(3R,6R)-1-{[2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 426.0,found 426.2 52

2-{2-[(3R,6R)-6-methyl-1-{[5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-olCalc′d 410.0, found 410.2 53

2-{2-[(3R,6R)-6-methyl-1-{[2-methyl-6- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-olCalc′d 410.0, found 410.2 54

2-{2-[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 426.0,found 426.2 55

2-{2-[(3R,6R)-6-methyl-1-{[6-methyl-2- (2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d411.0, found 411.2 56

2-{2-[(3R,6R)-1-{[2- (methoxymethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4- yl}propan-2-ol Calc′d 373.0,found 373.2 57

2-{2-[(3R,6R)-6-Methyl-1-(pyrazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 369.2, found 369.4 58

2-{2-[(3R,6R)-6-Methyl-1-{[3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d397.2, found 397.4 59

2-{2-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3- triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3- triazol-4-yl}propan-2-ol Calc′d397.2, found 397.4 60

2-(2-{(3R,6R)-1-[(2-Cyclopropylpyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-2H- 1,2,3-triazol-4-yl)propan-2-olCalc′d 370.2, found 370.4

EXAMPLE 61

1-{2-[(3R,6R)-1-{[2-(2,2-Difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl1 ethanol Step 1: Methyl2-((3R,6R)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate (9)

To a solution of (2R,5R)-benzyl 5-(4-(methoxycarbonyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidi-l-carboxylate (600 mg, 1.67 mmol)in THF (20 mL) at RT was added Pd/C (100 mg, 10 wt %). The resultingmixture was stirred under a H₂ atmosphere for 20 h, filtered andconcentrated in vacuo to give the title compound (334 mg) as an oil,used directly in the next step. LRMS m/z (M+H) 225.1 found, 225.1required.

Step 2: Methyl2-((3R,6R)-1-(2-(2,2-difluoroethoxy)nicotinoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate(10)

To a solution of the product from step 1 (330 mg, 1.47 mmol) in DCM (5mL) was added TEA (445 mg, 4.41 mmol), HATU (615 mg, 1.62 mmol) and2-(2,2-difluoroethoxy) nicotinic acid (298 mg, 1.47 mmol). The resultingmixture was stirred at 30° C. for 16 h. cooled to RT, brine (20 mL)added and the mixture extracted with DCM (20 mL×3). The organic layerswere combined, dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica (10%-30% EtOAc inpetroleum ether) to give the title compound (600 mg) as an oil. LRMS m/z(M+H) 410.2 found, 410.2 required.

Step 3: (2-((3R ,6R)-1-(2-(2,2-Difluoroethoxy)nicotinoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylicacid (11)

To a solution of the product from step 2 (600 mg, 1.47 mmol) in THF (5mL) and water (5 mL) was added LiOH·H2O (308 mg, 7.35 mmol). Theresulting mixture was stirred at RT for 4 h, diluted with water andextracted with EtOAc (10 mL×1). The aqueous phase was adjusted to pH˜6with HCl (2M) and extracted with EtOAc (30 mL×3). The organic layerswere combined, dried over MgSO₄, filtered and concentrated in vacuo togive the title compound (610 mg) as an oil. LRMS m/z (M+H) 396.2 found,396.1 required.

Step 4:2-((3R,6R)-1-(2-(2,2-Difluoroethoxy)nicotinoyl)-6-methylpiperidin-3-yl)-N-methoxy-N-methyl-2H-1,2,3-triazole-4-carboxamide(12)

To a solution of the product from step 3 (600 mg, 1.51 mmol) in DCM (10mL) was added TEA (715 mg, 7.08 mmol), N,O-dimethylhydroxylaminehydrochloride(207 mg, 2.13 mmol) and HATU (809 mg, 2.13 mmol). Theresulting mixture was stirred 4 h at 30° C., cooled to RT andconcentrated in vacuo to remove most of solvent. The residue waspurified by chromatography on silica (50% EtOAc in petroleum ether) togive the title compound (580 mg) as a solid. LRMS m/z (M+H) 439.4 found,439.2 required.

Step 5:1-(2-((3R,6R)-1-(2-(2,2-Difluoroethoxy)nicotinoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazol-4-yl)ethanone(13)

To a solution of the product from step 4 (200 mg, 0.46 mmol) in THF (5mL) at −20° C. was added MeMgBr solution (0.5 mL, 3M, 1.5 mmol)dropwise. The resulting mixture was stirred at 0° C. for lh, aqueousNH₄Cl (5mL) added and extracted with EtOAc (20 mL×3). The organic layerswere combined, dried over MgSO₄, filtered and concentrated in vacuo togive the title compound (150 mg) as an oil. LRMS m/z (M+H) 394.2 found,394.2 required.

Step 6:1-{2-[(3R,6R)-1-{[2-(2,2-Difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl1 ethanol (Example 61)

To a solution of the product from step 5 (100 mg, 0.25 mmol) in THF(3mL) at −20° C. was added iPrMgBr solution (0.83 mL, 3M, 2.5 mmol)dropwise. The resulting mixture was warmed from −20 to 0° C. over 4h,aqueous NH₄Cl (5 mL) added and extracted with EtOAc (20 mL×3). Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC togive the title compound (30 mg) as a solid. LC-MS m/z (M+H) 396.2 found,396.2 required.

EXAMPLE 62

2-{5-Methyl-2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-olStep 1: Ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (15)

To a solution of ethyl but-2-ynoate (6.0 g, 0.0536 mol) in CH₃CN (20 mL)was added TMSN₃ (15.4 g, 0.134 mol). The resulting mixture was stirredat 90° C. for 30 h, cooled to RT and concentrated in vacuo. The residuewas purified by chromatography on silica (0˜50% EtOAc in petroleumether) to give the title compound (700 mg) as a solid. LRMS m/z (M+H)156.1 found, 156.1 required.

Step 2: Ethyl 2-((3R ,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylate (16)

To a solution of the product from step 1 (570 mg, 3.65 mmol),(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5S)-5-hydroxy-2-methylpiperidin-1-yl)methanone(1.04 g, 3.65 mmol) and Ph₃P (2.06 g, 7.29 mmol) in THF (15 mL) at 0° C.was added DIAD (1.9 g, 7.29 mmol). The mixture was stirred at RT for 16h, concentrated in vacuo and the residue purified by chromatography onsilica (0˜70% EtOAc in petroleum ether) to give the title compound (1.37g) as a solid. LRMS m/z (M+H) 424.2 found, 424.2 required.

Step 3:2-{5-Methyl-2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl}carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol(Example 62)

To a solution of CeCl₃ (145 mg, 0.59 mmol) in THF (2 mL) at 0° C. wasadded MeMgBr (2.0 mL, 3 M, 5.9 mmol). The resulting mixture was stirredat 70° C. for 2h, cooled to −20° C. and the product from step 2 (500 mg,1.18 mmol) in THF (6 mL) added. The mixture was stirred at −20° C. for30 min and then at RT for 16 h, saturated aq. NH₄Cl added and themixture extracted with EtOAc (30 mL×3). The organic layers werecombined, dried over Na₂SO₄, filtered, concentrated in vacuo and theresidue purified by preparative HPLC to give the title compound (9.4 mg)as a solid. LRMS m/z (M−OH) 392.2, (M+H) 410.2 found, 410.2 required.

EXAMPLE 63

2-{5-Methyl-2-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-olStep 1: (2R,5R)-Benzyl5-(4-(ethoxycarbonyl)-5-methyl-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carboxylate(17)

To a solution of ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (800 mg,5.16 mmol, Example 60, step 1), (2R,5S)-benzyl5-hydroxy-2-methylpiperidine-1-carboxylate (1.4 g, 5.68 mmol) and Ph₃P(2.71 g, 10.3 mmol) in THF (15 mL) at 0° C. was added DIAD (2.7 g, 10.3mmol) dropwise. The resulting mixture was stirred at RT for 8 h under N₂atmosphere, concentrated in vacuo and the residue was purified bychromatography on silica (0˜50% EtOAc in petroleum ether) to give thetitle compound (1.50 g) as an oil. LRMS m/z (M+H) 387.1 found, 387.2required.

Step 2: (2R,5R)-Benzyl5-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carboxylate(18)

To a solution of MeMgBr (2.4 mL, 3M, 7.2 mmol) in dry THF (1 mL) at −20°C. was added the product from step 1 (700 mg, 1.81 mmol) in THF (7 mL)dropwise. The resulting mixture was stirred at RT for 4 h, saturated aq.NH₄Cl added and the mixture extracted with EtOAc (20 mL×3). The organiclayers were combined, dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (400 mg) as an oil. LRMS m/z (M+H)373.2, (M−OH) 355.3 found, 373.2 required.

Step 3:2-(243R,6R)-6-Methylpiperidin-3-yl)-2H-1,2,3-triazol-4-yl)propan-2-ol(19)

To a solution of the product from step 2 (300 mg, 0.804 mmol) in MeOH(10 mL) was added Pd/C (150 mg, 10 wt %). The resulting mixture wasstirred under a balloon of H₂ for 2 h, the mixture was filtered andconcentrated in vacuo to give the title compound (150 mg) as an oil,which was used directly without further purification. LRMS m/z (M+H)239.1 found, 239.2 required.

Step 4:2-{5-Methyl-2-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol(Example 63)

To a solution of HATU (84 mg, 0.220 mmol), 2-isopropoxynicotinic acid(35 mg, 0.191 mmol (35 mg, 0.191 mmol), DIEA (76 mg, 0.588 mmol) in DMF(3 mL) was added the product from step 3 (35 mg, 0.147 mmol) in DMF (1mL). The resulting mixture was stirred at RT for 16 h and purifieddirectly by preparative-HPLC to give the title compound (25 mg) as asolid. LRMS m/z (M+H) 402.1, (M−OH) 384.2 found, 402.2 required.

The following compounds were prepared according to the methodologyherein and the general procedure of step 4 provided in Example 63. Thestarting materials are either commercially available or may be preparedas described in the synthesis of intermediates, or may be prepared fromcommercially available reagents using conventional reactions well knownin the art.

Ex. Structure Name Mass [M + H]+ 64

2-{2-[(3R,6R)-1-{[2-(2,2- Difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3- yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 424.2 (M + H), found 406.1 (M − OH), 446.1 (M +Na) 65

2-(2-{(3R,6R)-1-[(2- Ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl- 2H-1,2,3-triazol-4-yl)propan-2-ol Calc′d388.2 (M + H), found 370.2 (M − OH), 410.1 (M + Na) 66

2-{2-[(3R,6R)-1-{[2- (Difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3- yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 409.2 (M + H), found 391.1 (M − OH), 431.1 (M +Na) 67

2-{5-Methyl-2-[(3R,6R)-6- methyl-1-{[2- (trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-2H- 1,2,3-triazol-4-yl}propan-2-ol Calc′d 427.2(M + H), found 409.1 (M − OH), 449.1 (M + Na) 68

2-{5-mMethyl-2-[(3R,6R)-6- methyl-1-{[2-(2,2,2-trifluoroethoxy)pyridin-3- yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 442.2 (M + H), found 424.1 (M −OH), 464.1 (M + Na) 69

2-(2-{(3R,6R)-1-[(2- Ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl- 2H-1,2,3-triazol-4-yl)propan-2-ol Calc′d387.2 (M + H), found 369.2 (M − OH), 409.1 (M + Na) 70

2-(2-{(3R,6R)-1-[(2- Cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl- 2H-1,2,3-triazol-4-yl)propan-2-ol Calc′d383.2 (M + H), found 365.2 (M − OH), 405.1 (M + Na) 71

2-{5-Methyl-2-[(3R,6R)-6- methyl-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3- yl]-2H-1,2,3-triazol-4-yl}propan- 2-olCalc′d 409.2 (M + H), found 391.2 (M − OH), 431.2 (M + Na) 72

2-{2-[(3R,6R)-1-{[4-Fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6- methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol Calc′d 428.2 (M + H), found 410.1 (M −OH), 450.1 (M + Na) 73

2-(5-Methyl-2-{(3R,6R)-6- methyl-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-2H- 1,2,3-triazol-4-yl)propan-2-ol Calc′d420.2 (M + H), found 420.2 (M + H), 442.2 (M + Na)

EXAMPLE 74

2-{2-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-tetrazol-5-yl}propan-2-olStep 1: Methyl2-((3S,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-tetrazole-5-carboxylate(20)

To a solution of compound 6 (Example 22, Step 2) (400 mg, 1.40 mmol),PPh₃ (733 mg, 2.80 mmol) and 1H-tetrazole-5-carboxylic acid methyl ester(239 mg, 1.68 mmol) in dry THF (4 mL) at RT was added DBAD (644 mg, 2.80mmol) and the resulting mixture stirred at 60° C. overnight. The cooledmixture was concentrated in vacuo and the residue purified bypreparative HPLC to give a mixture of the title compound (46.3 mg) andregioisomeric triazole substitution product as a solid. LRMS m/z (M+H)397.1 found, 397.2 required.

Step 2:2-{2-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-tetrazol-5-yl}propan-2-ol(Example 74)

To a solution of the crude product from step 1 (200 mg, 0.49 mmol) indry THF (4 mL) at 0° C. was added a solution of CH₃MgBr (0.49 mL, 3 M,1.47 mmol) dropwise. The resulting mixture was stirred for 1 h, thenwater (2 mL) added and the mixture extracted with EtOAc (5 mL×3). Thecombined organic layers were dried over MgSO₄, filtered and the filtrateconcentrated in vacuo. The residue was purified by preparative HPLC togive desired product (20.7 mg) as an oil. LRMS m/z (M+H) 397.2 found,397.2 required.

EXAMPLE 75

2-{1-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-olStep 1:(3S,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-ylmethanesulfonate(21)

To a solution of compound 6 (Example 22, Step 2) (2.0 g, 7.2 mmol) andDIEA (1.81 g, 14.4 mmol) in DCM (40 mL) at 0° C. was added MsCl (1.6 g,14.4 mmol) dropwise. The mixture was stirred at RT for 3 hrs, water (10mL) added and the mixture extracted with DCM (5 mL×3). The combinedorganic phases were washed with brine (5 mL), dried over Na₂SO₄,filtered and the filtrate concentrated in vacuo to give the titlecompound (2.5 g) as a solid. LRMS m/z (M+H) 365.1 found, 365.1 required.

Step 2: Ethyl1-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-1H-pyrazole-4-carboxylate(22)

To a suspension of NaH (53 mg, 1.3 mmol, 60 wt % in oil) in DMF (6 mL)at RT was added ethyl 1H-pyrazole-4-carboxylate (154 mg, 1.1 mmol) andthe mixture was stirred at RT for 30 min. A solution of the product fromstep 1 (400 mg, 1.1 mmol) in DMF (2 mL) was added and the resultingmixture stirred at 60° C. overnight. The cooled mixture was treated withwater (1 mL), filtered, and the filtrate purified by preparative HPLC toprovide the title compound (85 mg). LRMS m/z (M+H) 409.1 found, 409.2required.

Step 3:2-{1-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 75)

To a solution of the product from step 2 (300 mg, 0.34 mmol) in THF (6mL) at 0° C. was added MeMgBr (0.74 mL, 3M 2.22 mmol). The mixture wasstirred overnight at RT, saturated aqueous NH₄Cl (1 mL) added andextracted with EtOAc (50 mL×3). The combined organic phases were washedwith brine (20 mL), dried over Na₂SO₄, filtered and the filtrateconcentrated in vacuo. The residue was purified by preparative TLC (10%methanol in DCM) to provide the title compound (220 mg). LRMS m/z (M+H)395.1 found, 395.2 required.

EXAMPLE 76

2-(1-{(3R,6R)-6-Methyl-1-[(2-propylphenyl)carbonyl]piperidin-3-yl}-1H-pyrazol-4-yl)propan-2-olStep 1: (2R,5S)-Benzyl2-methyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (23)

To a solution of (2R,5S)-benzyl5-hydroxy-2-methylpiperidine-l-carboxylate (1.01 g, 4 mmol) TEA (1.01 g,10 mmol) in DCM (5 mL) at 0° C. was added MsCl (916 mg, 8 mmol). Theresulting mixture was stirred at RT for 2 h, water added and extractedwith DCM (5 mL×3). The combined organic layers were washed with brine (5mL×2), dried over Na₂SO₄, filtered and the filtrate concentrated invacuo to give the title compound (1.21 g) as an oil, used withoutfurther purification. LRMS m/z (M+H) 328.1 found, 328.2 required.

Step 2: (2R ,5R)-B enzyl 5-(4-(ethoxyc arbonyl)-1H-pyrazol-1-yl)-2-methylpip eridine-1-carboxylate (24)

To a solution of the product from step 1 (500 mg, 1.50 mmol) in DMF(20.0 mL) at RT were added Cs₂CO₃ (975 mg, 3.00 mmol) and1-1H-pyrazol-4-yl) propan-l-one (420 mg, 3 mmol). The mixture wasstirred at 80° C. under N₂ overnight, cooled to RT, diluted with water(10 mL) and extracted with EtOAc (50.0 mL×3). The combined organiclayers was washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by preparative TLC (33%EtOAc in petroleum ether) to give the title compound (450 mg) as asolid. LRMS m/z (M+H) 372.1 found, 372.2 required.

Step 3: (2R,5R)-Benzyl5-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate(25)

To a solution of the product from step 2 (450 mg, 1.20 mmol) in THF (20mL) at 0° C. was added CH₃MgBr solution (4.0 mL, 3 M, 12 mmol). Themixture was stirred at RT for 1 h, diluted with saturated aq. NH₄Clsolution, and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered, concentrated in vacuo and theresidue purified by preparative TLC (50% EtOAc in petroleum ether) togive the title compound (350 mg) as an oil. LRMS m/z (M+H) 358.3 found,358.2 required.

Step 4: 2-(143R,6R)-6-Methylpiperidin-3-yl)-1H-pyrazol-4-yl)propan-2-ol(26)

A mixture of the product from step 3 (350 mg, 0.98 mmol) and palladium(10 wt % on activated carbon, 100 mg) in degassed MeOH (10 mL) wasstirred overnight under an atmosphere of hydrogen. The degassed mixturewas filtered and concentrated in vacuo and the residue purifiedchromatography on silica (10% methanol in DCM) to give the titlecompound (240 mg) as an oil. LRMS m/z (M+H) 224.3 found, 224.2 required.

Step 5:2-(1-{(3R,6R)-6-Methyl-1-[(2-propylphenyl)carbonyl]piperidin-3-yl1-1H-pyrazol-4-yl)propan-2-ol(Example 76)

A solution of the product from step 4 (50 mg, 0.21 mmol),2-propylbenzoic acd (52 mg, 0.30 mmol) and HATU (122 mg, 0.32 mmol) inDMF/Et₃N (3 mL/0.2 mL) was stirred at RT overnight. The mixture waspurified directly by preparative HPLC to give the title compound (44 mg)as a solid. LRMS m/z (M-OH) 352.2 found, (M+H) 370.2 required.

The following compounds were prepared according to the methodologyherein and the general procedure of Example 76. The starting materialsare either commercially available or may be prepared as described in thesynthesis of intermediates, or may be prepared from commerciallyavailable reagents using conventional reactions well known in the art.

Mass Ex. Structure Name [M + H]+ 77

2-(1-{(3R,6R)-1-[(2- Ethoxyphenyl)carbonyl]-6- methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol Calc′d 372.2 (M + H), found 354.2 (M − OH) 78

2-(1-{(3R,6R)-1-[(2- Cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H- pyrazol-4-yl)propan-2-ol Calc′d 368.2 (M + H),found 350.1 (M − OH) 79

2-{1-[(3R,6R)-1-{[2-(2,2- Difluoroethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4- yl}propan-2-ol Calc′d 408.2 (M + H),found 390.2 (M − OH) 80

2-{1-[(3R,6R)-6-Methy-1-{[2-(2,2,2- trifluoroethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan- 2-ol Calc′d 426.2 (M + H), found408.1 (M − OH) 81

2-{1-[(3R,6R)-6-Methyl-1-{[2-(1- methylethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan- 2-ol Calc′d 386.2 (M + H), found368.2 (M − OH) 82

2-{1-[(3R,6R)-6-Methyl-1-{[2-(1- methylethyl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol Calc′d 370.2 (M + H), found 352.2 (M −OH) 83

2-{1-[(3R,6R)-6-Methyl-1-{[2- (trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4- yl}propan-2-ol Calc′d 412.2 (M + H), found394.14 (M − OH) 84

2-{1-[(3R,6R)-1-{[2- (Difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol- 4-yl}propan-2-ol Calc′d 394.2 (M +H), found 376.1 (M − OH) 85

2-{1-[(3R,6R)-1-({2-[(1S)-2,2- Difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 404.2 (M +H), found 386.3 (M − OH) 86

2-{1-[(3R,6R)-1-({2-[(1R)-2,2- Difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 404.2 (M +H), found 386.3 (M − OH) 87

2-(1-{(3R,6R)-1-[(2- Cyclobutylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4- yl)propan-2-ol Calc′d 382.2 (M + H),found 364.2 (M − OH) 88

2-{1-[(3R,6R)-6-Methyl-1-({2- [(trifluoromethyl)sulfanyl]phenyl}carbonyl)piperidin-3-yl]-1H-pyrazol-4- yl}propan-2-ol Calc′d 428.2 (M +H), found 410.1 (M − OH) 89

2-(1-{(3R,6R)-1-[(2-Ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}- 1H-pyrazol-4-yl)propan-2-ol Calc′d373.2 (M + H), found 355.1 (M − OH) 90

2-{1-[(3R,6R)-6-Methyl-1-{[2-(1H- pyrazol-1-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 395.2(M + H), found 377.1 (M − OH) 91

2-{1-[(3R,6R)-1-{[4-Fluoro-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol- 4-yl}propan-2-ol Calc′d 413.2 (M +H), found 385.1 (M − OH) 92

2-(1-{(3R,6R)-6-Methyl-1-[(2- phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-1H- pyrazol-4-yl)propan-2-ol Calc′d 405.2(M + H), found 387.1 (M − OH) 93

2-{1-[(3R,6R)-6-Methyl-1-{[2-(1H- pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]- 1H-pyrazol-4-yl}propan-2-ol Calc′d394.2 (M + H), found 376.2 (M − OH) 94

2-{1-[(3R,6R)-6-Methyl-1-{[2-(2,2,2- trifluoroethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 427.2(M + H), found 409.1 (M − OH) 95

2-{1-[(3R,6R)-6-Methyl-1-{[3-(1H- pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 396.2(M + H), found 378.1 (M − OH) 96

2-(1-{(3R,6R)-1-[(2-Cyclopropyl-6- methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4- yl)propan-2-ol Calc′d 399.2 (M + H),found 381.1 (M − OH) 97

2-{1-[(3R,6R)-6-Methyl-1-{[2-(1- methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 387.2(M + H), found 369.2 (M − OH) 98

2-{1-[(3R,6R)-1-{[2-(2,2- Difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]- 1H-pyrazol-4-yl}propan-2-ol Calc′d409.2 (M + H), found 391.2 (M − OH) 99

2-{1-[(3R,6R)-1-{[2-(2,2- Difluoroethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4- yl}propan-2-ol Calc′d 392.2 (M + H),found 374.3 (M − OH) 100

2-(1-{(3R,6R)-1-[(2-Cyclobutyl-6- methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4- yl)propan-2-ol Calc′d 413.3 (M + H),found 395.3 (M − OH) 101

2-{1-[(3R,6R)-6-Methyl-1-{[3-(2H- 1,2,3-triazol-2-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H- pyrazol-4-yl}propan-2-ol Calc′d 397.2(M + H), found 379.1 (M − OH)

EXAMPLES 102 AND 103(1R)-2,2,2-Trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyllcarbonyl}piperidin-3-yl}-1H-pyrazol-4-yl}ethanol

-   Scheme for the preparation of Example 102 and Example 103:

(1R)-2,2,2-Trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-ylH-pyrazol-4-yl}ethanol(1S)-2,2,2-Trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanolStep 1:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-methylpiperidin-1-yl)methanone(27)

To a solution of compound 22 (Example 73, Step 2) (150 mg, 0.37 mmol) intoluene (5 mL) was added DIBAL-H (0.74 mL, 0.74 mmol) dropwise at −78°C. under nitrogen. The resulting mixture was allowed to warm to RT andstirred for 1 h. Methanol (5 mL) was added slowly to the mixture and themixture then concentrated in vacuo. The residue was purified bypreparative TLC (50% EtOAc in petroleum ether) to give the titlecompound (100 mg) as an oil. LRMS m/z (M+H) 367.3 found, 367.2 required.

Step 2: 1-((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-1H-pyrazole-4-carbaldehyde(28)

A solution of the product from step 1 (100 mg, 0.27 mmol) and DMP (116mg, 0.27 mmol) in dry DCM (10 mL) was stirred at RT for 0.5 h. Themixture was filtered and the filtrate concentrated in vacuo to give thetitle compound (80 mg) as an oil, which was used in the next stepwithout further purification. LRMS m/z (M+H) 365.2 found, 365.2required.

Step 3: (1R)-2,2,2-Trifluoro-1-{ 1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol(Example 102)(1S)-2,2,2-trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol(Example 103)

To a solution of the product from step 2 (80 mg, 0.22 mmol) in dry THF(10 mL) was added CsF (33 mg, 0.22 mmol) and TMSCF₃ (94 mg, 0.66 mmol)and the resulting mixture stirred at RT overnight. The reaction mixturewas concentrated in vacuo and the residue purified by preparative HPLCand then chiral SFC (OZ 250×30 mm I.D.,5 um, CO₂/MeOH (0.1%)NH₃·H2O=85/15 at 60 mL/min) to give the Example 102 (47 mg, fastereluting isomer in SFC) as a solid and Example 103 (27 mg, slower elutingisomer in SFC) as a solid. Example 102: LRMS m/z (M+H) 435.1 found,435.2 required. Example 103: LRMS m/z (M+H) 435.1 found, 435.2 required.

EXAMPLES 104, 105 AND 106

1,1,1-Trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 104)(2R)-1,1,1-Trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 105) (2S)-1,1,1-Trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 106) Step 1: Ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (29)

To a solution of ethyl 1H-pyrazole-4-carboxylate (5 g, 40.0 mmol) in THF(150 mL) at 0° C. was added NaH (1.92 g, 48.0 mmol, 60 wt % in oil),followed by SEMCl (8.00 g, 48.0 mmol). The mixture was stirred at RT for5 h, diluted with water (50 mL), and extracted with EtOAc (40 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound (8.00 g) as an oil.LRMS m/z (M+H) 271.1 found, 271.1 required.

Step 2: 1((2-(Trimethylsilypethoxy)methyl)-1H-pyrazole-4-carboxylic acid(30)

To a solution of the product from step 1 (8 g, 31.5 mmol) in EtOH (100mL) was added water (5.00 mL) and LiOH (3.75 g, 156 mmol). The mixturewas stirred at RT overnight and concentrated in vacuo to remove most ofsolvent. The residue was poured into water (40.0 mL) and extracted withEtOAc (20 mL×3). The aqueous layer was acidified with 1N HCl, andextracted with EtOAc (40.0 mL×3). The combined organic layers, driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound (6.50 g) as an oil, used without further purification. LRMS m/z(M+H) 243.1 found, 243.1 required.

Step 3:N-Methoxy-N-methyl-142-(trimethylsilypethoxy)methyl)-1H-pyrazole-4-carboxamide(31)

To a solution of the product from step 2 (6.5 g, 26.9 mmol) in DCM (200mL) at RT were added HOBT (3.63 g, 26.7 mmol), EDC (10.3g, 53.7 mmol),DIEA (10.3 g, 80.6 mmol) and N, O-dimethylhydroxylammonium (5.20 g, 53.7mmol). The mixture was stirred at RT for 4 h, poured into water (50 mL),and extracted with EtOAc (30 mL×3). The organic layers were combined,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by s chromatography on silica(10% EtOAc in petroleum ether) togive the title compound (6.0 g) as an oil. LRMS m/z (M+H) 286.1 found,286.2 required.

Step 4:N-Methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide(32)

To a solution of the product from step 3 (4.0 g, 14.0 mmol) in THF (50mL) at 0° C. was added MeMgBr (18.0 mL, 3M, 54.0 mmol). The mixture wasstirred at RT overnight, diluted with saturated aq. NH₄Cl solution andextracted with EtOAc (20 mL×3). The organic layers were combined, driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by chromatography on silica (10% EtOAc in petroleum ether) togive the title compound (2.6 g) as an oil. LRMS m/z (M+H) 241.1 found,241.1 required.

Step 5:N-Methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide(33)

To a solution of the product from step 4 (1.0 g, 4.12 mmol) in THF (50mL) at 0° C. were added TMSCF₃ (0.71 mL, 5.00 mmol), CsF (0.94 g, 6.18mmol) and TBAF (1.3 g, 4.21 mmol). The resulting mixture was allowed towarm to RT overnight, diluted with water (10 mL), and extracted withEtOAc (30 mL×3). The organic layers were combined, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica (10% EtOAc in petroleum ether) to give thetitle compound (420 mg) as an oil. LRMS m/z (M+H) 311.1 found, 311.1required.

Step 6:N-Methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide(34)

To a solution of the product from step 5 (420 mg, 1.35 mmol) in THF (15mL) at RT was added TBAF (427 mg, 1.35 mmol). The mixture was stirred at60° C. for 3 d, cooled to RT, and concentrated in vacuo. The residue waspurified by preparative HPLC to give the title compound (200 mg) as anoil. LRMS m/z (M+H) 180.9 found, 181.0 required.

Step 7:1,1,1-Trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 104)

To a solution of the product from step 6 (100 mg, 0.56 mmol) in DMF (5mL) at RT were added Cs₂CO₃ (361 mg, 1.11 mmol) and compound 21 (Example73, Step 1) (202 mg, 0.56 mmol). The mixture was stirred at 80° C. for14 h, cooled to RT, filtered and purified by preparative HPLC to givethe title compound (70.0 mg) as a solid. LRMS m/z (M+H) 449.2 found,449.2 required.

Step 8:(2R)-1,1,1-Trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 105) (2S)-1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 106)

The product from step 6 (140 mg, 0.31 mmol) was separated by chiral SFC(OD 250×30mm I.D.,5um, CO₂/MEOH (0.1%) NH₃·H₂O=60/40 at 50 mL/min) togive Example 105 (51 mg, faster eluting isomer in SFC) as a solid andExample 106 (63 mg, slower eluting isomer in SFC) as a solid. Example105: LRMS m/z (M+H) 449.2 found, 449.2 required. Example 106:LRMS m/z(M+H) 449.1 found, 449.2 required.

EXAMPLES 107 AND 1082-{3-Methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 107)

EXAMPLE 1082-{5-Methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol

-   Scheme for the preparation of Example 107 and Example 108:

2-{3-Methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 107)2-{5-Methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 108) Step 1: Ethyl1-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-3-methyl-1H-pyrazole-4-carboxylate(35) and ethyl 1-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-5-methyl-1H-pyrazole-4-carboxylate(36)

To a suspension of NaH (33 mg, 0.82 mmol, 60 wt % in oil) in DMF (6 mL)at RT was added ethyl 1H-pyrazole-4-carboxylate (85 mg, 0.55 mmol). Themixture was stirred at RT for 30 min, then a solution of compound 21(Example 73, Step 1) (200 mg, 0.55 mmol) in DMF (2 mL) added. Themixture was stirred at 60° C. overnight, cooled to RT, diluted withwater (1 mL) and filtered. The filtrate was purified by preparative HPLCto give the product (140 mg) as a solid. LRMS m/z (M+H) 423.1 found,423.2 required.

Step 2:2-{3-Methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 107) and2-{5-methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol(Example 108)

To a solution of the product from step 1 (100 mg, 0.24 mmol) in THF (3mL) at 0° C. was added CH₃MgBr solution (0.47 mL, 3M, 1.42 mmol). Themixture was stirred at RT overnight, diluted with saturated aq. NH₄Clsolution, and extracted with EtOAc (20 mL×3). The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by preparative HPLC to to give Example 107 (22 mg)as an oil and Example 108 (13 mg) as an oil. Example 107: LRMS m/z (M+H)409.2 found, 409.2 required. Example 108: LRMS m/z (M+H) 409.2 found,409.2 required.

The following table shows representative data for the compounds of theExamples as orexin receptor antagonists as determined by the assaysdescribed herein.

hOX2R FLIPR hOXIR FLIPR Example IC₅₀ (nM) IC₅₀ (nM) 1 13.8 1155 2 16.2483 3 1065 >10000 4 15.9 8106 5 71.3 >10000 6 14.9 2459 7 51.7 >10000 81781.0 >10000 9 30.0 >10000 10 26.0 >10000 11 20.0 2554 12 31.3 >1000013 14.3 >10000 14 15.9 8788 15 32.6 >10000 16 22.8 >10000 17 16.1 367718 15.0 >10000 19 12.1 2804 20 24.6 >10000 21 18.0 >10000 22 8.5 733 2346.9 >10000 24 511.8 >10000 25 7.5 594 26 86.7 >10000 27 17.9 505 2869.7 54 29 362.5 >10000 30 138.5 >10000 31 36.4 >10000 32 89.6 >10000 3318.4 2564 34 36.8 >10000 35 592.6 >10000 36 62.9 >10000 37 75.2 >1000038 27.5 >10000 39 27.1 >10000 40 86.7 >10000 41 172.9 >10000 42622.1 >10000 43 108.6 >10000 44 897.2 >10000 45 51.4 >10000 4656.4 >10000 47 45.7 >10000 48 136.5 >10000 49 29.1 2829 50 126.5 >1000051 67.4 >10000 52 59.8 3086 53 31.1 1809 54 53.3 >10000 55 221.9 >1000056 308.1 >10000 57 489.1 >10000 58 44.9 >10000 59 400.5 >10000 60608.5 >10000 61 681.3 >10000 62 12.5 1251 63 15.9 3350 64 8.8 2986 6515.1 2933 66 9.6 3060 67 10.1 1149 68 6.9 1516 69 7.9 1952 70 8.8 760 719.3 2713 72 15.2 1289 73 17.4 2463 74 44.9 >10000 75 21.6 >10000 7652.3 >10000 77 120.8 >10000 78 25.5 >10000 79 127.0 >10000 80165.4 >10000 81 89.8 >10000 82 347.0 >10000 83 31.4 >10000 84464.1 >10000 85 9.4 2635 86 152.2 >10000 87 49.3 3291 88 15.2 7929 89283.0 >10000 90 33.6 >10000 91 18.8 >10000 92 195.4 >10000 9392.7 >10000 94 37.0 >10000 95 271.0 >10000 96 1602.0 >10000 97239.8 >10000 98 58.8 >10000 99 38.4 >10000 100 60.8 >10000 101479.2 >10000 102 123.7 >10000 103 102.0 >10000 104 13.4 2011 105 9.42728 106 10.6 2062 107 13.8 339 108 73.2 3367

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: X is N or C(R⁷); Y is N or C(R⁶), wherein when Y is N then X isalso N; A is selected from the group consisting of phenyl, naphthyl andheteroaryl; R^(1a), R^(1b) and R^(1c) are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1 (wherein if mis 0 or n is 0, a bond is present) and where the alkyl is unsubstitutedor substituted with one or more sub stituents selected from R⁴, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R⁴, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R⁴, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R⁴, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where the phenylor naphthyl is unsubstituted or substituted with one or moresubstituents selected from R⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R⁴,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R⁴, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R⁴, (e)C₃-₆cycloalkyl which is unsubstituted or substituted with R⁴, (f)phenyl, which is unsubstituted or substituted with R⁴, and (g)heterocycle, which is unsubstituted or substituted with R⁴, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R³ is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl, whichis unsubstituted or substituted with one or more substituents selectedfrom R⁴; R⁴ is selected from the group consisting of: (1) hydroxyl, (2)halogen, (3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH₂, (7) —NH—C₁₋₆alkyl, (8) —NO₂, (9) phenyl,(10) heterocycle, (11) —CO₂H, and (12) —CN; R⁵ is selected from thegroup consisting of: (1) hydrogen, (2) halogen, (3) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂,—NH—C_(l-6)alkyl, —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl isunsubstituted or substituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH,(4) C₃₋₆cycloalkyl, which is unsubstituted or substituted withC₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,—(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is unsubstituted orsubstituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH, (5) —O—C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl or phenyl,and (6) —(C═O)O—C₁₋₆alkyl, (7) —CN, (8) —(C═O)NH₂, (9)—(C═O)NH—C₁₋₆alkyl, and (10) —(C═O)NH—O—C₁₋₆alkyl; R⁶ is selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) C₁₋₆alkyl, whichis unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl,—NH₂, —NH—C₁₋₆alkyl, —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl isunsubstituted or substituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH,(4) C₃₋₆cycloalkyl, which is unsubstituted or substituted withC₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,—(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is unsubstituted orsubstituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH, (5) —O—C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl or phenyl,and (6) —(C═O)O—C₁₋₆alkyl, (7) —CN, (8) —(C═O)NH₂, (9)—(C═O)NH—C₁₋₆alkyl, and (10) —(C═O)NH—O—C₁₋₆alkyl; R⁷ is selected fromthe group consisting of: (1) hydrogen and (2) C₁₋₆alkyl, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1 ofthe formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein Y is C(R⁶).
 5. The compound of claim 1, wherein X is N and Yis C(R⁶).
 6. The compound of claim 1, wherein X is C(R⁷) and Y is C(R⁶).7. The compound of claim 1, wherein X is N and Y is N.
 8. The compoundof claim 1 or a pharmaceutically acceptable salt thereof wherein R^(1a),R^(1b) and R^(1c) are independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, (5)—O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (6) —CN, and (7) heteroaryl, wherein heteroaryl isselected from triazolyl, tetrazolyl, oxazolyl, pyrrolyl, imidazolyl,indolyl, pyridyl, and pyrimidinyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 9. The compoundof claim 1 or a pharmaceutically acceptable salt thereof wherein R^(1a),R^(1b) and R^(1c) are independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen or methoxy, (4) —O—C₁₋₆alkyl, which isunsubstituted or substituted with halogen, (5) —C₃₋₆cycloalkyl, whereinsaid —C₃₋₆cycloalkyl is selected from the group consisting ofcyclopropyl and cyclobutyl, which is unsubstituted or substituted withhalogen or CN; (6) heterocyclyl, wherein heterocyclyl is selected fromthe group consisting of pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl,pyridyl, and pyrrolidinyl, which is unsubstituted or substituted withC₁₋₆alkyl; (7) phenyl; and (8) —S—C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen.
 10. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein R³ is methyl or ethyl.11. The compound of claim 1 or a pharmaceutically acceptable saltthereof wherein A is selected from the group consisting of phenyl,pyridyl, thienyl, pyrazinyl, and pyrazolo[1,5-a]pyridinyl.
 12. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁵ is selected from the group consisting of: (1) —C(CH₃)₂OH, (2)—CH(OH)CF₃, (2) —CH(OH)CH₃, (2) —C(OH)(CF₃)CH₃, (3) —C(═O)OCH₃, (4)bromo, and (5) phenyl.
 13. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R⁶ is hydrogen or methyl.
 14. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁷ is hydrogen or methyl.
 15. A compound which is selected fromthe group consisting of:1-(2-((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile;[1,1′-biphenyl]-2-yl((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-propylpyridin-3-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-propylphenyl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-sopropylphenyl)methanone;(2-cyclopropylphenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;(2-(difluoromethoxy)pyridin-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;methyl3-((2R,5R)-5-(4-(2-hy-droxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)picolinate;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethyl)phenyl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanone;2-{2-[(3R,6R)-6-methyl-1-({2-[(trifluoromethyl)sulfanyl]phenyl}carbonyl)piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;(2-ethoxyphenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperi-din-1-yl)methanone;(2-(2,2-difluoroethoxy)pyridin-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopro-poxypyridin-3-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)phenyl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-isopropoxyphenyl)methanone;(2-(2,2-difluoroethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone;methyl2-((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carbonyl)benzoate;(2-(difluoromethoxy)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;2-{2-[(3R,6R)-1-({2-[(1S)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-({2-[(1R)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;methyl 2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-2H-1,2,3-triazole-4-carboxylate;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-(4-phenyl-2H-1,2,3-triazol-2-yl)piperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-bromo-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;(5-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidin-1-yl)methanone;2-{2-[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[5-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[4-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[4-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(2-{(3R,6R)-6-methyl-1-[(3-pyridin-2-ylpyrazin-2-yl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[3-(1H-pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[2-(2-methoxyethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[6-methoxy-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(2-{(3R,6R)-6-methyl-1-[(2-pyrrolidin-1-ylphenyl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;2-(2-{(3R,6R)-6-methyl-1-[(3-phenoxyphenyl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;2-{2-[(3R,6R)-1-{[2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[2-(methoxymethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-Methyl-1-(pyrazolo[1,5-a]pyridin-7-ylcarbonyl)piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-Methyl-1-{[3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(2-{(3R,6R)-1-[(2-cyclopropylpyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;1-{2-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-2H-1,2,3-triazol-4-yl}ethanol;2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(2-[(3R,6R)-1-{[(2-ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;2-{2-[(3R,6R)-1-{[2-(difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(2-{(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;2-(2-{(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol;2-{5-methyl-2-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]-2H-1,2,3-triazol-4-yl}propan-2-ol;2-{2-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-5-methyl-2H-1,2,3-triazol-4-yl}propan-2-ol;2-(5-methyl-2-{(3R,6R)-6-methyl-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-2H-1,2,3-triazol-4-yl)propan-2-ol;2-{2-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-2H-tetrazol-5-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-6-methyl-1-[(2-propylphenyl)carbonyl]piperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-(1-{(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-(1-{(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethyl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-1-{[2-(difluoromethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-1-({2-[(1S)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-1-({2-[(1R)-2,2-difluorocyclopropyl]phenyl}carbonyl)-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-1-[(2-cyclobutylphenyl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-({2-[(trifluoromethyl)sulfanyl]phenyl}carbonyl)piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-1-[(2-ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-6-methyl-1-[(2-phenylpyridin-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[3-(1H-pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-1-[(2-cyclopropyl-6-methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[2-(1-methylethoxy)pyridin-3-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol; 2-{1-[(3R,6R)-1-{[2-(2,2-difluoroethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-(1-{(3R,6R)-1-[(2-cyclobutyl-6-methoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}-1H-pyrazol-4-yl)propan-2-ol;2-{1-[(3R,6R)-6-methyl-1-{[3-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;(1R)-2,2,2-trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol;(1S)-2,2,2-trifluoro-1-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}ethanol;1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;(2R)-1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;(2S)-1,1,1-trifluoro-2-{1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;2-{3-methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;and2-{5-methyl-1-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]-1H-pyrazol-4-yl}propan-2-ol;or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 17. (canceled) 18.(canceled)
 19. A method for enhancing the quality of sleep in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 1 ora pharmaceutically acceptable salt thereof.
 20. A method for treatinginsomnia in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof. 21.(canceled)